RxPG News : AIDS

NIH launches 2009 H1N1 influenza vaccine trials in HIV-infected pregnant women

Fri, 09 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The first clinical trials to test whether the 2009 H1N1 influenza vaccine can safely elicit a protective immune response in pregnant women launched yesterday, and a trial to conduct the same test in HIV-infected children and youth will begin next week. The International Maternal Pediatric Adolescent AIDS Clinical Trials Group is conducting the studies, which are sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health.

These studies are important because HIV infection and pregnancy both increase the risk for a poor immune response to the normal 15-microgram dose of seasonal influenza vaccine given to the general population, says NIAID Director Anthony S. Fauci, M.D. Moreover, children, young people and pregnant women are at higher risk for more severe illness from the 2009 H1N1 influenza virus than other groups, and HIV-infected individuals in these populations may be particularly vulnerable.

Because of the increased vulnerability of these populations, these trials are testing whether doses of licensed 2009 H1N1 influenza vaccine that are higher than doses being tested in other groups can safely elicit protective immune responses in HIV-infected children, youth and pregnant women, adds Lynne Mofenson, M.D., chief of the Pediatric, Adolescent and Maternal AIDS Branch in NICHD.

One trial will enroll 130 HIV-infected pregnant women ages 18 to 39 years who are in their second or third trimester (14 to 34 weeks) of pregnancy. The other trial will enroll 140 children and youth aged 4 to 24 years who were infected with HIV at birth.

Thirty-five sites and eight sub-sites across the United States and Puerto Rico are eligible to conduct the trials. Each volunteer will receive two 30-microgram doses of 2009 H1N1 influenza vaccine 21 days apart. (In contrast, the NIAID studies of 2009 H1N1 influenza vaccine in HIV-uninfected children, youth and pregnant women are testing doses of 15 and 30 micrograms.)

Safety data will be collected and monitored closely by the study investigators and an independent safety monitoring committee. The strength and longevity of the immune response elicited by the vaccine will be gauged in several ways.

The study team will take blood samples from the pregnant women after each dose and three and six months after delivery to measure the concentration of antibodies the women produce against 2009 H1N1 influenza virus and how strong that antibody response remains over time. After the women give birth, study staff will sample umbilical cord blood to measure the concentration of maternal antibodies against the H1N1 virus that were transferred to the infants through the placenta. The study team also will collect small blood samples from the infants at 3 and 6 months of age to measure their level of maternally derived antibody protection from the virus over time. The infants will not receive vaccine.

Similarly, in children and young people, the strength and longevity of the immune response will be gauged by testing blood samples taken 21 days after the first dose, 10 days after the second dose, and six months after entering the study.

The vaccine, manufactured by Novartis Vaccines and Diagnostics, contains inactivated 2009 H1N1 influenza virus, so it is impossible to become infected with the virus by receiving the vaccine. The vaccine does not contain adjuvant, a substance added to some vaccines to improve the body's response to vaccine.

Research on seasonal influenza vaccine and vaccines for other diseases in HIV-infected and other populations suggest that higher doses of vaccine tend to elicit stronger immune responses. These stronger responses, in turn, increase the concentration of protective antibodies in the bloodstream, which likely is beneficial to both the vaccinated individual and, if pregnant, to her fetus. This is the rationale for testing whether higher doses of licensed 2009 H1N1 influenza vaccine elicit a protective immune response in HIV-infected individuals and whether that protection is transferred to the fetuses of vaccinated pregnant women.

HIV vaccine regimen demonstrates modest preventive effect in Thailand clinical study

Thu, 24 Sep 2009 03:59:36 PST

( from http://www.rxpgnews.com ) In an encouraging development, an investigational vaccine regimen has been shown to be well-tolerated and to have a modest effect in preventing HIV infection in a clinical trial involving more than 16,000 adult participants in Thailand. Following a final analysis of the trial data, the Surgeon General of the U.S. Army, the trial sponsor, announced today that the prime-boost investigational vaccine regimen was safe and 31 percent effective in preventing HIV infection.

These new findings represent an important step forward in HIV vaccine research, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, which provided major funding and other support for the study. For the first time, an investigational HIV vaccine has demonstrated some ability to prevent HIV infection among vaccinated individuals. Additional research is needed to better understand how this vaccine regimen reduced the risk of HIV infection, but certainly this is an encouraging advance for the HIV vaccine field.

We thank the trial staff in Thailand and the United States for their years of effort in successfully conducting this study and the study participants and the people of Thailand for their long-standing support of HIV vaccine research, Dr. Fauci adds.

The Thai Phase III HIV vaccine study, also known as RV144, opened in October 2003. The placebo-controlled trial tested the safety and effectiveness of a prime-boost regimen of two vaccines: ALVAC-HIV vaccine (the primer dose), a modified canarypox vaccine developed by Sanofi Pasteur, based in Lyon, France, and AIDSVAX B/E vaccine (the booster dose), a glycoprotein 120 vaccine developed by Vaxgen Inc., and now licensed to Global Solutions for Infectious Diseases (GSID), based in South San Francisco, Calif. The vaccines are based on the subtype B and E HIV strains that commonly circulate in Thailand. The subtype B HIV strain is the one most commonly found in the United States.

Led by principal investigator Supachai Rerks-Ngarm, M.D., of the Thai Ministry of Public Health's Department of Disease Control, the study was sponsored by the U.S. Army in collaboration with NIAID, Sanofi Pasteur and GSID. The trial, conducted in the Rayong and Chon Buri provinces of Thailand, enrolled 16,402 men and women ages 18 to 30 years old at various levels of risk for HIV infection. Study participants received the ALVAC HIV vaccine or placebo at enrollment and again after 1 month, 3 months, and 6 months. The AIDSVAX B/E vaccine or placebo was given to participants at 3 and 6 months. Participants were tested for HIV infection every 6 months for 3 years. During each clinic visit, they were counseled on how to avoid becoming infected with HIV.

In the final analysis, 74 of 8,198 placebo recipients became infected with HIV compared with 51 of 8,197 participants who received the vaccine regimen. This level of effectiveness in preventing HIV infection was found to be statistically significant. The vaccine regimen had no effect, however, on the amount of virus in the blood of volunteers who acquired HIV infection during the study.

The Thai study demonstrates why the HIV vaccine field must take a balanced approach to conducting both the basic research needed to discover and design new HIV vaccines and, when appropriate, testing candidate vaccines in people, says Margaret I. Johnston, Ph.D., director of NIAID's Vaccine Research Program within the Division of AIDS. Both avenues provide critical information that will continue to help us better understand what is needed to develop a fully protective HIV vaccine.

NIAID and the collaborating partners are working with other scientific experts to determine next steps, including additional research of the RV144 vaccine regimen and the need to consider the impact of these new findings on other HIV vaccine candidates.

Individuals who acquired HIV infection while participating in the Thai trial have been provided access to HIV care and treatment, including highly active antiretroviral therapy based on the guidelines of the Thai Ministry of Public Health.

Clinical trial of antiretroviral-based HIV prevention strategies for women now under way

Wed, 16 Sep 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A new, large-scale clinical trial is examining whether antiretroviral medications normally used to treat HIV infection can also prevent HIV infection in women when applied as a vaginal gel or taken as oral tablets once daily.

The study, called Vaginal and Oral Interventions to Control the Epidemic (VOICE) or MTN-003, will involve up to 5,000 HIV-uninfected women at risk for HIV infection in four African countries. The trial will test the safety and efficacy of two different HIV prevention strategies: an investigational microbicide gel containing the antiretroviral drug tenofovir, and oral tablets containing tenofovir or a combination of tenofovir and emtricitabine known by the brand name Truvada. The tablets would be taken prior to exposure in an approach known as pre-exposure prophylaxis, or PrEP. Testing a microbicide and PrEP in the same trial will enable scientists to directly compare the two strategies in terms of their safety and acceptability.

Notably, the VOICE study is the first efficacy study of an investigational microbicide in which participants apply the gel once daily rather than shortly before sexual intercourse. If found effective, this approach would allow participants to choose whether to use the gel in association with sexual activity or at another time of day, permitting greater privacy and convenience of use.

We need multiple, scientifically proven HIV prevention strategies acceptable to different populations to effectively combat the spread of the virus, and PrEP and microbicides are two promising approaches that we are actively pursuing, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). The VOICE study is designed to answer multiple crucial questions about these experimental interventions, with an emphasis on protecting women from HIV.

NIAID is sponsoring and funding the trial with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the National Institutes of Health. Co-sponsors are Gilead Sciences Inc. of Foster City, Calif., and CONRAD of Arlington, Va. The NIH-funded Microbicide Trials Network is conducting the study.

Women make up half of all people worldwide living with HIV, and in sub-Saharan Africa, women represent nearly 60 percent of adults living with the virus. In most cases, women become infected with HIV through sexual intercourse with an infected male partner. An effective microbicide or PrEP regimen could give women an HIV prevention method they control. This would be particularly helpful in situations where it is difficult or impossible for women to refuse sex or negotiate condom use with their male partners.

The VOICE study is being conducted at 14 sites in South Africa, Uganda, Zambia and Zimbabwe. The Phase IIb study, which will last approximately three and a half years, is being led by Zvavahera Mike Chirenje, M.D., of the University of Zimbabwe in Harare, and Jeanne Marrazzo, M.D., M.P.H., of the University of Washington in Seattle. The sexually active, HIV-uninfected women ages 18 to 45 participating in the study will be randomly assigned to one of five regimens, each performed once daily:

ART therapy for babies, mothers safely reduces HIV transmission

Wed, 22 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Giving daily antiretroviral syrup to breastfeeding infants or treating their HIV-infected mothers with highly active antiretroviral drugs is safe and effective in preventing mother-to-child HIV transmission through breast milk, a study led by University of North Carolina at Chapel Hill investigators has found.

This is an exciting development, said Charles van der Horst, M.D., a professor in the UNC School of Medicine and the study's lead investigator. We may be able to spare mothers in the developing world a horrible choice by offering them an effective method for preventing transmission of HIV during breastfeeding.

These findings, from investigators at UNC-Chapel Hill, UNC Project-Malawi in Lilongwe, Malawi and the U.S. Centers for Disease Control and Prevention (CDC), were presented July 22 at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa (Abstract .WELBC1 - Late Breaker C 16:30 - 17:30 Session Room 2).

Approximately 420,000 infants are infected with HIV annually, half through breast milk. HIV-infected women in resource-constrained areas face a terrible dilemma: provide the many health and nutritional benefits of breast milk but face a 20 percent chance of transmitting the virus to their baby or choose costly formula, which relies on an unsafe water supply and carries a higher risk of morbidity and mortality, and avoid transmitting HIV.

The Breastfeeding, Antiretrovirals and Nutrition (BAN) study is the only large-scale, randomized trial comparing infant prophylaxis or maternal treatment to an enhanced standard-of-care arm in the prevention of HIV transmission through breast milk. The study was conducted in Lilongwe, Malawi at a single site. Investigators randomly assigned at total of 2,367 mother-infant pairs to one of three treatment arms. For both the interventions, the probability of HIV-infection was significantly lower than in the enhanced control arm.

Of the randomized infants, 4.9 percent were found to be HIV positive at birth. Among infants who were HIV-free at one week old, 6.4 percent on the enhanced control arm were infected by 28 weeks, compared to 3.0 percent of the infants on the maternal treatment arm and 1.8 percent of the infants who received daily nevirapine syrup. Upon examining the probability of HIV infection or death by 28 weeks postpartum, 7.6 percent of the infants on the enhanced control arm were HIV-infected or died compared to 4.7 percent of the infants on the maternal treatment arm, and 2.9 percent of the infants on the infant prophylaxis arm.

The BAN study results give global and national policy makers the choice of which intervention (maternal or infant antiretroviral intervention) to implement based on the conditions and resources in their particular setting. We hope to see these results translated quickly into program and policy.

New method for HIV testing holds promise for developing world

Tue, 21 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) DURHAM, NC -- A new technique that detects the HIV virus early and monitors its development without requiring refrigeration may make AIDS testing more accessible in sub-Saharan Africa.

According to UNAIDS, sub-Saharan Africa accounts for almost a third of all new HIV infections and AIDS-related deaths globally. Yet there may be many people who do not get tested due to the high cost of treatment and minimal access to health care.

Duke Physician John Crump and a team of researchers recently completed a 10-month experiment at two remote sites in Tanzania. They examined Tanzanian infants born to HIV-infected parents and people with known HIV infections who needed monitoring of their viral loads. Viral load is a measurement used to diagnose HIV infection or determine the severity of HIV infection.

In the largest field study of its kind, researchers compared viral load measurements by using the current standard of frozen plasma and the alternative method of dried blood spots (DBS). The samples were measured at a central lab at the Kilimanjaro Christian Medical Centre in Moshi, some 250 and 350 kilometers away from the two study sites.

The Duke study found a strong correlation between viral load values in plasma and DBS, making the two testing approaches comparable. This finding could lay the foundation for a new way of testing for and monitoring patients with HIV in the future, according to Dr. John Bartlett, Duke Global Health Institute Associate Director for Research.

The sooner infants are diagnosed with HIV, the sooner they can receive life-prolonging medications to treat the disease. The infection cannot be detected in newborns using the typical HIV antibody test, and must be detected with other techniques, including viral load testing.

Viral load testing is also the optimal way for monitoring HIV infection in patients with known infections, especially for those receiving treatment.

But few labs in Tanzania perform the viral load procedure, and blood samples must be transported long distances to specialized medical facilities for testing. Plasma requires continuous cold storage during shipment, which can be challenging or impossible in resource-limited settings. This may prevent people from getting tested or result in inaccurate tests.

Dried blood spots offer the advantage of not requiring cold storage, says Bartlett, who also points out that this method may result in lower total health care costs. Before using it for care and treatment programs, it will need further evaluation. But, this is the largest field study of DBS's done to date, and the results appear promising.

Treatment with highly active antiretroviral therapy for HIV helps control Hepatitis B

Wed, 15 Jul 2009 14:12:13 PST

( from http://www.rxpgnews.com ) Prolonged use of highly active antiretroviral therapy (HAART) to treat people infected with both HIV and hepatitis B (HBV) helps to better control the hepatitis B infection and could delay or prevent liver complications, according to a new study by researchers at Wake Forest University School of Medicine.

Researchers also found that patients who had higher levels of a common liver enzyme upon beginning treatment for HIV-HBV co-infection were at an increased risk of being diagnosed with cirrhosis within the first few years of follow-up. Cirrhosis is a disease that scars the liver, progressively shutting it down. The enzyme is one released into the bloodstream after liver damage.

"One of the most interesting findings was the confirmation that a simple marker, such as transaminase levels before treatment, is useful in identifying patients at higher risk of developing HBV-related complications in a few years," said lead researcher Marina Núñez, M.D., Ph.D., an assistant professor in the Section on Infectious Diseases, in the Department of Internal Medicine at the School of Medicine.

The study is appears in the May/June issue of HIV Clinical Trials, published today.

HBV is a contagious liver disease, contracted in the same way as HIV – through intravenous drug use, sexual contact or mother-to-newborn transmission. Left untreated, it can lead to fatal liver disease or liver cancer.

HIV increases the activity of HBV, speeds the progression of related liver disease and might decrease the effectiveness of treatments for HBV.

But Núñez and Tsan Lee, a medical student at the School of Medicine, found that prolonged use of highly active antiretroviral therapy, including one or more drugs active against HBV, can lead to clearance of the HBV infection in co-infected patients. HAART is the treatment for HIV infection, consisting of a combination of drugs commonly known as the "cocktail."

For the study, researchers reviewed medical records of patients seen in an adult HIV clinic between 1990 and 2008. They included in the study all patients with positive HIV antibody, hepatitis B and at least three months of follow-up care on record.

Of the 72 patient charts reviewed – primarily black males with a median age of 39 and advanced HIV disease at the time of diagnosis – 64 of the patients received HAART that included drugs effective in treating HBV, for a median duration of one year. The researchers were looking for whether the patients were diagnosed with liver complications such as cirrhosis and liver cancer over the course of treatment, and whether the chronic HBV infection improved.

Analysis showed that receiving HAART combined with HBV treatment for a longer period of time was significantly associated with reduced and, in some cases cleared, chronic HBV infection.

Núñez said these findings "stress the importance of good control of the HIV and HBV infections through maintained compliance with HAART including drugs to treat HBV.

"In HBV-HIV patients with the elevated enzyme levels that signal liver damage, it is even more important to control the HBV infection in an attempt to decrease the risks of complications. Those patients should also be more closely screened for liver complications."

Probiotics can increase effectiveness of some antibiotic therapies

Thu, 09 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Antimicrobial treatments for bacterial vaginosis (BV) are effective, but taking lactobacillus tablets alongside metronidazole antibiotic therapy increases effectiveness over taking this antibiotic alone, according to a Cochrane Systematic Review. The researchers also concluded that intravaginal lactobacillus was as effective as oral metronidazole, although they did note unexplained drop-outs from the trials.

BV is a very common vaginal infection. Traditionally, antibiotics in tablet or gel form have been given to treat the disease, but some have unpleasant side effects. BV is usually a mild disease and can pass unnoticed but is associated with an increased risk of HIV transmission.

Treating BV could help reduce susceptibility of women to HIV. Therefore it is important, particularly in the developing world, to establish the most effective and appropriate forms of treatment, says lead researcher Oyinlola Oduyebo, of the Department of Medical Microbiology and Parasitology at the University of Lagos in Lagos Nigeria.

The researchers reviewed 24 trials involving 4,422 people. The antibiotics clindamycin and metronidazole both cured BV in over 90% of cases within two to three weeks, although there was a high rate of relapse. Side effects of metronidazole included nausea and a metallic taste in the mouth. However, it is the cheaper option and therefore likely to remain the most widely used in developing countries. Lactobacillus probiotic taken alongside metronidazole and taken intravaginally both showed significant effectiveness. Hydrogen peroxide and triple sulphonamide cream were not effective.

There are a range of good treatments for BV, but the high relapse rates require more attention and indicate that we need more research into other agents that can increase their effectiveness, said Oduyebo. We also need to understand why so many people dropped out of the Lactobacillus trials as this suggests there are unreported adverse effects.

Indian American helps design vaginal ring to prevent HIV transmission

Thu, 18 Jun 2009 12:27:35 PST

( from http://www.rxpgnews.com ) An Indian American endocrinologist has helped develop a vaginal ring that would prevent conception and transmission of HIV infection, by releasing multiple types of non-hormonal agents and microbicides.

Worldwide, there are about five million new infections and three million deaths every year caused by HIV/AIDS alone.

If proven successful in future clinical trials, the vaginal ring could empower women to protect themselves from unintended pregnancy and sexually transmitted diseases.

The ring may also someday represent a novel method to prevent STDs for those with aversion to currently available methods, with hormonally derived active agents, or with allergies to latex condoms.

'This device is a new approach to birth control, because it avoids the long-term use of hormonal methods that have been associated with increased risk of certain cancers,' said Brij Saxena, study co-author and professor of reproductive biology and endocrinology at Weill Cornell Medical College -.

'At the same time, this is the first device to simultaneously offer the possibility to prevent unintended pregnancy and HIV transmission,' said Saxena, who did his B.Sc, M.Sc and Ph.D from Lucknow University - in 1949, 1951 and 1954, respectively.

'No one has ever conquered a viral epidemic with treatment, so prevention is the most effective option. Ideally, an HIV vaccine is the most desirable method, but that is not foreseeable in the near future,' explained Jeffrey Laurence, study co-author and physician at New York-Presbyterian Hospital/WCMC.

'The next best thing would be something that would prevent infection and put the power in the susceptible female partner's control. That's the potential a device such as this can offer.'

The vaginally inserted ring is incorporated with multiple antiviral drugs that prevent HIV infection and are time-released over a period up to 28 days, said a WCMC release.

'The compounds in the device are natural materials that are already approved by the US Food and Drug Administration for use in humans,' explained Saxena.

The results were published recently in AIDS.

One step closer to the HIV vaccine

Sun, 17 May 2009 11:05:28 PST

( from http://www.rxpgnews.com ) A research team may have broken the stubborn impasse that has frustrated the invention of an effective HIV vaccine, by using an approach that bypasses the usual path followed by vaccine developers. By using gene transfer technology that produces molecules that block infection, the scientists protected monkeys from infection by a virus closely related to HIV—the simian immunodeficiency virus, or SIV—that causes AIDS in rhesus monkeys.

"We used a leapfrog strategy, bypassing the natural immune system response that was the target of all previous HIV and SIV vaccine candidates," said study leader Philip R. Johnson, M.D., chief scientific officer at The Children's Hospital of Philadelphia. Johnson developed the novel approach over a ten-year period, collaborating with K. Reed Clark, Ph.D., a molecular virologist at Nationwide Children's Hospital in Columbus, Ohio.

The study appeared today in the online version of Nature Medicine.

Johnson cautioned that many hurdles remain before the technique used in this animal study might be translated into an HIV vaccine for humans. If the technique leads to an effective HIV vaccine, such a vaccine may be years away from realization.

Most attempts at developing an HIV vaccine have used substances aimed at stimulating the body's immune system to produce antibodies or killer cells that would eliminate the virus before or after it infected cells in the body. However, clinical trials have been disappointing. HIV vaccines have not elicited protective immune responses, just as the body fails on its own to produce an effective response against HIV during natural HIV infection.

The approach taken in the current study was divided into two phases. In the first phase, the research team created antibody-like proteins (called immunoadhesins) that were specifically designed to bind to SIV and block it from infecting cells. Once proven to work against SIV in the laboratory, DNA representing SIV-specific immunoadhesins was engineered into a carrier virus designed to deliver the DNA to monkeys. The researchers chose adeno-associated virus (AAV) as the carrier virus because it is a very effective way to insert DNA into the cells of a monkey or human.

In the second part of the study, the team injected AAV carriers into the muscles of monkeys, where the imported DNA produced immunoadhesins that entered the blood circulation. One month after administration of the AAV carriers, the immunized monkeys were injected with live, AIDS-causing SIV. The majority of the immunized monkeys were completely protected from SIV infection, and all were protected from AIDS. In contrast, a group of unimmunized monkeys were all infected by SIV, and two-thirds died of AIDS complications. High concentrations of the SIV-specific immunoadhesins remained in the blood for over a year.

Further studies need to be conducted if this technique is to become an actual preventive measure against HIV infection in people, Johnson said. "To ultimately succeed, more and better molecules that work against HIV, including human monoclonal antibodies, will be needed," he and his co-authors conclude. Finally, added Johnson, their approach may also have potential use in preventing other infectious diseases, such as malaria.

Humanized mouse infected with HIV vaginally and rectally allows testing

Sun, 19 Apr 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The humanized mouse developed by Dr. J. Victor Garcia-Martinez has allowed the University of Texas Southwestern physician-scientist to conduct HIV/AIDS studies that would have been impossible without such a small animal model of HIV infection. The virus only infects humans and chimpanzees, which are protected as endangered species.

But because the new mouse model is a chimera, with a human immune system, it can be infected. Last year, using these humanized mice, a team of scientists led by Dr. Garcia-Martinez demonstrated that antiretroviral drugs given before and after exposure to HIV could prevent vaginal transmission of the virus. That suggests the possibility that women at high risk of HIV infection might one day be able to take a pill on a regular basis. And, since the drugs tested are already available, having gone through the long and complex approval process, that day might be sooner rather than later.

On Sunday, April 19, Dr. Garcia-Martinez tells fellow scientists attending Experimental Biology 2009 in New Orleans that the team is now using the mouse model to obtain evidence that these same approaches apply to protecting men.

Dr. Garcia-Martinez's presentation, updating improvements in the humanized mouse and in the progress of this and other work using the mouse model of human HIV/AIDS infection, is part of the scientific program of the American Society for Biochemistry and Molecular Biology.

First created in 2006, by Dr. Garcia and colleagues at UT Southwestern and the University of Minnesota, the humanized mouse used in these studies represented a new frontier in the preclinical testing of experimental drugs. Early mice models of disease were created by breeding mice that were immunodeficient in order that they would not reject grafts of human tissue. The big advance in the mouse created by Dr. Garcia-Martinez's group is that the mouse develops a human immune system, thanks to transfer of fetal human liver and thymic tissue cells that repopulate the bone marrow, which produces more cells.

The problem with using animals other than humans and chimpanzees for HIV/AIDS studies had been that the other animals, including ordinary mice, never become infected even when exposed to massive amounts of the virus. But the Garcia-Martinez mouse model (called BLT for bone marrow-liver-thymus) can easily be infected with HIV by both rectal and vaginal transmission, since both areas of the mouse body contain human cells.

With a long term-goal to investigate novel approaches to prevent HIV transmission, the team began with male to female infection. Women are at higher risk of infection during heterosexual sex with an infected partner, and women worldwide account for more than half of the estimated 11,000 newly acquired infections every day, with a majority of those transmissions occurring via the vaginal route. However, says Dr. Garcia-Martinez, male to male sexual contact accounts for a high proportion of the HIV/AIDS cases in the United States and rates of such transmission continue to rise, despite extensive educational campaigns.

Dr. Garcia-Martinez believes these statistics clearly reflect an urgent need to devise and implement potential interventions that could prevent both vaginal and rectal HIV-1 transmission especially among high-risk populations. The humanized mouse model provides an increasingly effective tool to move in that direction.

Education slowing AIDS in sub-Saharan Africa

Sun, 22 Mar 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Increased schooling across sub-Saharan Africa may be lowering new HIV infections among younger adults, according to sociologists, suggesting a shift in a decades-long trend where formal education is considered an AIDS risk factor.

While education in general has a positive impact on global public health, when it comes to HIV and AIDS in sub-Saharan Africa, education has had a completely opposite effect.

During the early stages of the HIV pandemic in the region, the disease passed unnoticed amidst the onslaught of other infections. When scientists took a closer look at the deadly new disease, they found that more often males with a higher than average education were contracting the disease.

Before the 1990s, in the impoverished regions of sub-Saharan Africa, even modest amounts of education afforded males higher income, more leisure time, and, for some males, greater access to commercial sex workers, explained David Baker, professor of education and sociology at Penn State and lead author of the study. HIV-infected higher-status males then spread the infection to both educated and uneducated women, which moved the disease into the general population.

Baker and his Penn State colleagues John Collins and Juan Leon, both graduate students, believe that information about AIDS that was already percolating in wealthier countries did not get to sub-Saharan Africa until the mid 1990s. AIDS was seen as a homosexual, urban disease and either neglect or active misinformation campaigns in some African countries ensured that the preventative effects of education never took root. But among younger people in the region, formal education is emerging as a major preventative factor against new infections. They report their findings in the current issue of the UNESCO journal Prospects.

There needs to be a very clear message, both to the donor community and to governments in sub-Saharan Africa, that expanding quality primary schools has to be a topmost priority, said Collins, co-author of the study. It will not only have economic benefits, but also health benefits.

To find what has happened recently to the link between formal education and HIV infections, the researchers analyzed data from surveys previously undertaken in 11 countries across the region between 2003 and 2005. They specifically looked at males ages 15 to 24, 25 to 34, and older than 35.

Survey participants were tested for HIV infection and interviewed about their education, social status, and sexual behavior.

The researchers argued that because the youngest members of the oldest group -- the 35 and older -- became sexually mature in the late 1980s, when there was little or no information about AIDS, higher education would show as a risk factor instead of a social vaccine.

Statistical analyses of the data suggest that in all 11 countries formal education had no effect on HIV infections in the oldest group, probably because many older adults, educated and uneducated have already been exposed to the virus and many have died. However, having some schooling did reduce the risk of HIV infections in the youngest group by up to 34 percent in Guinea, Malawi, Senegal, Cameroon, Ghana, and Kenya.

At 24 years, the oldest member of this young group reached sexual maturity in the mid 1990s, when there was already widespread knowledge that HIV and AIDS could be contracted through unprotected sex and intravenous drug use, explained Baker.

The researchers hypothesize that, reasoning skills gained in school by younger adults play a preventative role against HIV in sub-Saharan Africa.

More educated people have the cognitive tools to make better sense out of facts presented to them, explained Baker. We have shown that when there is sufficient information, and no misinformation, people with education adopt healthy strategies to avoid infections.

The Penn State researchers caution that while a large number of deaths in the early stages of the HIV pandemic could mask the true effects of education in the oldest group, the findings hold key policy implications for turning education into a social vaccine against HIV in sub-Saharan Africa.

According to Baker, AIDS is a complicated disease and it can only be tackled effectively by providing people with an everyday, accurate working theory of how the disease is transmitted. We are telling the governments that increased literacy is an explicit prevention strategy against HIV because it will help stop pandemics, he said.

The Penn State researcher also asks non-governmental organizations to reevaluate their educational programs.

The kind of information being supplied by NGOs is scandalous because it is so simplistic and minimalist, particularly for low-educated people, that they are not going to figure this disease out in time to prevent their own infection, Baker added.

UCSF Transgender HIV Prevention Center funded to provide primary care information

Thu, 12 Mar 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The UCSF Center of Excellence for Transgender HIV Prevention (CoE) has received a grant from The California Endowment that will expand access to information and resources on providing culturally competent health care to trangender individuals.

Many physicians are in dire need of the information that we will make available in order to provide the highest quality and most appropriate healthcare to transpeople. This grant will improve the quality of medical care received by transpeople in California and around the nation, said UCSF CoE director, JoAnne Keatley, MSW.

In addition, this grant brings the CoE into the healthcare arena and takes us closer to our vision of becoming a comprehensive center for transgender health, added Keatley.

The CoE was launched in 2007 to provide leadership, capacity building, professional training, policy advocacy, research development, and resources to increase access to culturally competent HIV prevention services for transgender people in California.

The establishment of the Center of Excellence in Transgender HIV Prevention was a historic event. This is the first time any state has funded a statewide effort to impact HIV among transpeople, the launching of the website provides access to the resources and information that providers need in order to deliver culturally competent, effective services, said Keatley.

The transgender community is currently experiencing the highest rates of HIV in many parts of California. In Los Angeles, studies have shown that between one quarter and one half of trans women in the county are living with HIV. In San Francisco, the percentage of trans women living with HIV is estimated to be between 16 and 60 percent. In San Diego, 15 percent of trans women are estimated to be HIV positive. And in one study in Alameda County, it was reported that 58 percent of the African American trans women who participated in the study were living with HIV.

The CoE receives funding from the California Department of Public Health, Office of AIDS.

Access to appropriate and sensitive primary health care is an important component of HIV prevention for transgender individuals, said Michelle Roland, MD, division chief of the Office of AIDS. The California Endowment's grant to expand access to transgender primary care information is an important step forward in our on-going efforts.

It is a collaborative partnership that combines the unique strengths and resources of a renowned training and capacity building institution, the UCSF Pacific AIDS Education and Training Center (PAETC), and an internationally recognized leader in HIV prevention research, the UCSF Center for AIDS Prevention Studies (CAPS).

Through PAETC we provide training and educational activities related to the clinical management of HIV. With this new grant, we can assist in ensuring that clinical providers provide appropriate care for transpeople in a welcoming environment, said CoE principal investigator, Michael Reyes, MD, MPH, from UCSF PAETC.

The CoE provides a vital role in disseminating essential information and best practices among caregivers and community based organizations across the state. The CoE's Community Advisory Board is drawn from community members throughout California and works to vigorously sustain the critical dialogue that needs to take place between a community facing a public health crisis and providers tasked with responding to that crisis, according to Reyes.

The Center provides consultation and technical assistance to community-based organizations that provide HIV prevention services to transpeople and we wish to improve or expand those services. We help agencies stay informed of research findings as they implement their programs and we learn from providers and the community about directions that future research should take to improve HIV prevention outcomes among transpeople, said Jae Sevelius, PhD, CoE co-principal investigator from the UCSF CAPS.

UCSF's Lesbian, Gay, Bisexual, Transgender Resource Center helped develop the proposal for the CoE.

Clinical trial finds microbicide promising as HIV prevention method for women

Thu, 05 Mar 2009 04:59:36 PST

( from http://www.rxpgnews.com ) March 5, 2009 -- A clinical trial involving more than 3,000 women in the U.S. and southern Africa demonstrates for the first time the promise of a vaginal microbicide gel for preventing HIV infection in women. According to findings presented at the Conference on Retroviruses and Opportunistic Infections (CROI), one 0.5 % dose of a microbicide designed to prevent HIV from attaching to cells in the genital tract, was 30% effective. While the results are encouraging, researchers on the study, known as HPTN 035, report that additional evidence is needed to determine more definitively its effectiveness.

These findings provide the first signal that a microbicide gel may be able to prevent women from HIV infection, says Salim S. Abdool Karim, MD, PhD, professor of clinical Epidemiology at Columbia University Mailman School of Public Health, pro vice-chancellor (research) at the University of KwaZulu-Natal in Durban, South Africa, and director the Center for the AIDS Program of Research in South Africa, who led the multi-center study for the U.S.-based Microbicide Trials Network (MTN). Indeed, for the millions of women at risk for HIV, especially young women in Africa, there is now a glimmer of hope. But these findings also indicate that more research is needed; we can't yet say that we have an effective microbicide.

Microbicides are substances intended to reduce or prevent the sexual transmission of HIV and other sexually transmitted infections when applied topically. Several candidate microbicides are being tested in clinical trials, although none is yet approved or available for use. Earlier trials have yielded disappointing results or were stopped prematurely.

Currently, women comprise half of all people worldwide living with HIV. In sub-Saharan Africa, women represent nearly 60 % of adults living with HIV, and in several southern African countries young women are at least three times more likely to be HIV-positive than young men. In most cases, women become infected with HIV through sexual intercourse with an infected male partner. Although correct and consistent use of male condoms has been shown to prevent HIV infection, women often cannot negotiate condom use with their male partners. An effective microbicide could provide women with an HIV prevention method they initiate.

HPTN 035 evaluated the safety and effectiveness of two candidate microbicides for preventing male-to-female sexual transmission of HIV. The study was conducted between February 2005 and September 2008 and involved 3,099 women at six sites in Africa and one in the United States. In Africa, the sites were located in Durban and Hlabisa, KwaZulu-Natal, South Africa; Harare, Zimbabwe; Lusaka, Zambia; Blantyre, Malawi; and Lilongwe, Malawi. The U.S. site was in Philadelphia.

I am particularly impressed by and grateful to the women who took part in HPTN 035, commented Sharon Hillier, PhD, vice chairman and professor, department of obstetrics and gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, and MTN principal investigator. We have reached an important milestone in HIV prevention research, and these women deserve credit for the success of the study.

High rate of HIV treatment interruption among newly released prison inmates

Wed, 25 Feb 2009 00:38:05 PST

( from http://www.rxpgnews.com ) Approximately 80 percent of HIV-infected Texas prison inmates did not fill an initial prescription for antiretroviral therapy within 30 days of their release from prison, potentially increasing their risk for harmful health consequences because of an interruption of treatment, according to a study in the February 25 issue of JAMA.

"The U.S. prison system has become an important front in the effort to treat and control the spread of human immunodeficiency virus (HIV) infection, serving as the principal screening and treatment venue for thousands of individuals with or at high risk for HIV infection who have limited access to community-based health care. Many inmates are offered HIV testing for the first time while incarcerated, and three-quarters of inmates with HIV infection initiate treatment during incarceration," the authors write.

Because the majority of former inmates are without private or public health insurance for the first several months after release, accessing antiretroviral therapy (ART) in a timely manner represents a challenge. "Those who discontinue ART at this time are at increased risk of developing a higher viral burden, resulting in greater infectiousness and higher levels of drug resistance, potentially creating reservoirs of drug-resistant HIV in the general community," they add. The extent to which HIV-infected inmates experience ART interruption following release from prison is unknown.

Jacques Baillargeon, Ph.D., of the University of Texas Medical Branch, Galveston, and colleagues conducted a study in the nation's largest state prison system to determine the proportion of HIV-infected inmates who filled a prescription for ART medication within 60 days following their release from prison. The study included all 2,115 HIV-infected inmates released from the Texas Department of Criminal Justice prison system between January 2004 and December 2007 who were receiving ART before release.

Among the entire study group, an initial prescription for ART medication was filled by 115 (5.4 percent) of the former inmates within 10 days of release, by 375 (17.7 percent) within 30 days, and by 634 (30.0 percent) within 60 days. The authors found that Hispanic and African American inmates were less likely to fill a prescription within 10 days and 30 days compared with non-Hispanic whites. Inmates with an undetectable viral load were more likely to fill a prescription than inmates with a detectable viral load at release. Inmates released on parole were more likely to fill a prescription within 30 days and 60 days than inmates with a standard, unsupervised release. Inmates who received formal assistance in completing an AIDS Drug Assistance Program application were more likely to fill a prescription than inmates who received no such assistance.

"In this 4-year study of HIV-infected inmates released from the nation's largest state prison system, we found that only 5 percent of released inmates filled a prescription for ART medications soon enough (i.e., within 10 days after release) to avoid treatment interruption," the authors write. In all of the subgroups examined, at least 90 percent of the former inmates experienced a treatment interruption; more than 70 percent had a treatment interruption that lasted at least 30 days, and more than 60 percent had a treatment interruption that lasted at least 60 days.

"These exceedingly high rates of treatment interruption suggest that most inmates face significant administrative, socioeconomic, or personal barriers to accessing ART when they return to their communities. Future prospective and in-depth qualitative studies are needed to more rigorously examine these barriers. Adequately addressing a public health crisis of this scale and complexity will require carefully coordinated efforts between academic institutions, the criminal justice system, and public health agencies," the researchers write. "In particular, greater coordination between state and local agencies, health care institutions, and community-based organizations is needed to reduce this high rate of treatment interruption among newly released inmates."

Case Western Reserve University faculty named 2009 NorTech Innovation Award winner

Mon, 23 Feb 2009 04:59:36 PST

( from http://www.rxpgnews.com ) NorTech, in partnership with Crain's Cleveland Business, today presented a 2009 NorTech Innovation Award to Eric J. Arts, Ph.D., for his development of a Biotech Platform to Detect, Monitor, and Treat Viral Diseases. Dr. Arts and his research team developed a set of diagnostic tests used by physicians and researchers to monitor the success of anti-HIV treatment by determining drug resistance and disease strength of the virus. The technology can also be used in academic research to better understand HIV/AIDS and to develop vaccines. Dr. Arts is an Associate Professor of Medicine in the Division of Infectious Diseases, Department of Medicine at Case Western Reserve University School of Medicine. He is also Director of the Uganda Laboratory Core for the Case Western Reserve University Center for Aids Research.

It is an honor to receive the prestigious NorTech Innovation Award, said Dr. Arts. My team and I appreciate this recognition of our decades of work and commitment to advancing the treatment and quality of life for patients with HIV/AIDS.

Dr. Arts is highly respected by his peers in the field of infectious disease. His research found that the heterogeneity of HIV type 1 has a significant impact on viral fitness, disease progression in the patient, emergence of drug resistance, and development of an effective vaccine. Although encompassing a broad range of topics, all of his research projects are related to HIV type 1 genetic diversity.

Dr. Arts and his laboratory are a source of great pride for the School of Medicine. Their work is an excellent example of our institution's focus on translational research which ultimately results in improved care for patients, said Pamela B. Davis, M.D., Ph.D., Dean, School of Medicine, Case Western Reserve University. We look forward to this technology's next generation of testing for conditions, such as hepatitis C, and the development of real-time influenza vaccines based on a season's dominant virus strains.

Since 2000, NorTech has been recognizing technology leaders working at the forefront of research, development, and technology commercialization in Northeast Ohio, said Dorothy C. Baunach, President and CEO, of NorTech. We believe the innovations being recognized today will lay the groundwork for building new technology industries for the future of our region.

Earlier this month, Case Western Reserve University and Diagnostic HYBRIDS Inc. signed an exclusive worldwide licensing agreement granting Diagnostic HYBRIDS rights to a novel yeast-based virus cloning technology invented by Dr. Arts. His technology is a step towards personalizing medicine based on the needs of each patient. In this case, physicians can use this assay to determine the effectiveness of a patient's anti-HIV medication. Compared with existing drug-resistance technology, Dr. Arts' technology is more sensitive, inexpensive, and provides better analysis of the body's response to medication.

UCSF symposium considers biomedical approaches to HIV/AIDS prevention

Thu, 12 Feb 2009 04:59:36 PST

( from http://www.rxpgnews.com ) New and emerging biomedical approaches to HIV/AIDS prevention will be the focus of a daylong symposium on February 24 sponsored by the UCSF-Gladstone Institute for Virology and Immunology Center for AIDS Research (CFAR) and the UCSF Center for AIDS Prevention Studies.

Defining new biomedical approaches capable of curbing the global HIV epidemic is a high priority. This symposium will provide a timely overview of the most promising advances, said Warner C. Greene, MD, PhD, director of the Gladstone Institute for Virology and Immunology (GIVI) and co-director of the UCSF-GIVI CFAR.

Use of antiretrovirals for HIV prevention in uninfected individuals at high risk for infection, herpes suppression, male circumcision and the successful treatment of HIV-infected individuals with antiretrovirals are some of the approaches that will be under discussion at the symposium.

With the setbacks in HIV vaccine development and a still expanding epidemic, we are forced to consider all options to prevent HIV transmission. Along with ongoing and critical efforts to understand and reduce behaviors of risk, we are deeply interested in how biologic barriers may be employed in effective prevention, said Paul A. Volberding, MD, UCSF-GIVI CFAR co-director and professor and vice-chair, UCSF Department of Medicine.

Antiretroviral therapies are extremely potent and convenient in reducing HIV replication and might be part of a comprehensive effort to couple treatment with prevention. In selected situations, antiretroviral therapy may be used solely as prevention in persons otherwise unable to avoid potential exposure to infection. These and other topics promise to generate a lively and informative debate, added Volberding.

In addition to examining biomedical approaches, the symposium will address topics related to the conduct of clinical trials investigating these approaches and issues associated with implementation and scale-up of biomedical prevention interventions once they have been proven effective in clinical trials.

Understanding the impact of behavioral issues such as consistent pill-taking or proper product usage as well as the difficulties of measuring these through trial participants' self reporting is crucial to successfully conducting clinical trials of biomedical approaches, said Stephen F. Morin, professor of medicine and director of the UCSF Center for AIDS Prevention Studies (CAPS).

Moreover, the symposium will address the social science components involved in the implementation and scale-up of interventions following positive results in a clinical trial. For instance, male circumcision trials have shown success in preventing HIV acquisition but, as we will discuss, there are significant cultural, social and behavioral considerations that must be addressed if the intervention is going to be successfully implemented, said Morin.

The symposium will be held at UCSF's Mission Bay campus at the Mission Bay Conference Center beginning at 9 a.m. The full program can be found, along with information about parking, mass transit and registration online at

Model of pre-exposure prophylaxis against HIV forecasts benefits, potential cost-effectiveness

Mon, 09 Feb 2009 04:59:36 PST

( from http://www.rxpgnews.com ) WHAT: For every two people who begin treatment for HIV infection globally, five others become newly infected. Therefore, preventing new HIV infections is the foremost strategy for ending the HIV/AIDS epidemic. One potential prevention strategy involves giving antiretroviral drug regimens to people who are at high risk for HIV to protect them from infection. Important questions about this experimental approach, known as pre-exposure prophylaxis (PrEP), remain unanswered, including, Could PrEP cut the lifetime risk of HIV infection? Would PrEP be cost-effective?

A new mathematical model of PrEP use in U.S. populations at high risk for HIV infection takes these and other questions into account and predicts the prevention strategy could substantially reduce the lifetime risk of HIV infection. According to the model, the cost-effectiveness of PrEP could vary substantially depending on the age of the target population, their risk behaviors, the annual rate of new HIV infections in the target population, and the efficacy and cost of antiretroviral PrEP drugs. These findings are reported by a team of scientists led by A. David Paltiel, Ph.D., of Yale University, and supported by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health and the National Institute on Drug Abuse, all part of the National Institutes of Health.

Dr. Paltiel says his team's model is the first to establish performance benchmarks that clarify the clinical, epidemiologic and economic circumstances under which PrEP would represent good patient care, good public health and good value.

To create their model, the researchers made several conservative assumptions: 1) PrEP is 50 percent effective; 2) the target population is American men who have sex with men who average 34 years of age; 3) 1.6 percent of this population becomes newly infected with HIV annually; and 4) the antiretroviral drugs (tenofovir and emtricitabine) cost $9,000 per year. With these parameters, the model predicts PrEP would cut the lifetime risk of HIV infection from 44 percent to 25 percent. However, the life expectancy of the target population from the time after beginning PrEP would increase by less than a year (from 39.9 years to 40.7 years) and PrEP would not be cost-effective by current U.S. standards. Yet with modest improvements in the efficacy of antiretrovirals used preventively, more realistic estimates of their cost (potentially as low as $900 per year), or a target population that is younger and at higher risk, the model predicts PrEP might be as cost-effective as other widely recommended public health and medical interventions in the United States. With large improvements in these parameters, the potential benefits of PrEP could be substantial, according to the model. For example, assuming PrEP will be 90 percent effective leads the predicted lifetime risk of HIV infection to fall from 44 percent to 6 percent.

Breast fed babies on Nevirapine prophylaxis are at risk of developing drug-resistant HIV

Mon, 05 Jan 2009 11:50:26 PST

( from http://www.rxpgnews.com ) Babies born to HIV-positive mothers and given the antiretroviral drug nevirapine through the first six weeks of life to prevent infection via breast-feeding are at high risk for developing drug-resistant HIV if they get infected anyway, a team of researchers report. But the investigators highlight the proven superiority of the six-week regimen in preventing mother-to-child HIV transmission in breast-fed infants.

In a study led by researchers at Johns Hopkins Children's Center, risks of drug resistance in the first year of life were compared in Indian infants getting a standard single dose of nevirapine at birth and those on the six-week regimen.

"While extended nevirpaine prophylaxis dramatically reduces HIV transmission during the first six weeks of life, our data show that if infection does occur, it will most likely be with strains resistant to nevirapine, making HIV much harder to treat early with nevirapine," says senior investigator Deborah Persaud, M.D., a pediatric HIV expert at Hopkins Children's. "But until other interventions become available, the extended nevirapine regimen remains a reasonable way to prevent infections through breast-feeding."

Published in the Jan.1 issue of Public Library of Science One (PLoSOne), the research report emphasized that in the developing world especially, where bottle feeding is not safe, too expensive or simply unavailable, the extended nevirapine therapy remains one of the best ways to reduce mother-to-child transmission of HIV through breast milk.

Given the high risk of death from HIV in infancy, the benefits of fewer infections still outweigh the risk of increased resistance, the researchers conclude.

The findings also suggest that because of their higher risk for acquiring resistant HIV strains, infants given extended courses of nevirapine—should they get infected—should receive treatment with protease inhibitors (PIs), which are effective against nevirapine-resistant strains.

"In the developing world testing for resistance is not available or too expensive," Persaud says, "so if extended nevirapine regimens become widespread, PIs should be made available as a first line of treatment early on for all infants who get infected despite prophylaxis."

The new report comes on the heels of two separate multi-center studies from Johns Hopkins and other institutions, published in 2008, showing that a six-week regimen with nevirapine or a 14-week regimen with nevirapine slashed the risk of HIV infection from breast-feeding by 46 percent and 66 percent, respectively.

For the current study, investigators analyzed samples from 74 Indian babies infected with HIV before, during or after birth. Of the 74 infants, 22 were infected before birth, 19 were infected during birth or during early breastfeeding (three to six weeks after birth) and 33 were infected during late breast-feeding (around six months after birth). Of the 19 infants infected through breastfeeding in the first six weeks of life, four were given daily nevirapine for six weeks, and 15 received a single dose at birth. All four babies on extended nevirapine developed resistant strains of the virus, while only four of the 15 given a single dose tested positive for resistant strains after infection.

It is important to keep in mind that while the risk of resistance is higher with extended nevirapine regimens once infection occurs, the risk of acquiring HIV with extended regimens is dramatically reduced, the investigators say. Thus, in the long run, extended nevirapine regimens do not lead to more resistant cases than the single-dose regimens because single-dose regimens also carry some risk of resistance and are also less effective in preventing new infections.

Indeed, when researchers compared resistance among infants infected during late breast-feeding, the gap in resistance risk virtually disappeared. Fifteen percent of the 13 infants given extended nevirapine developed resistance, and so did 15 percent of the 20 infants who received a single dose of the drug.

When investigators used more sensitive assays to detect nevirapine-resistant mutations that are normally not detected by standard tests, the proportion of infants with resistant strains who had received single-dose nevirapine went up from 38 percent to 59 percent among the 29 infants who got the single dose, but remained unchanged in the group receiving the six-week regimen, 92 percent of 12. Likewise, the proportion of infants testing positive for resistance went up in the group infected after six weeks of age. In that group, 31 percent of 13 infants on the extended regimen tested positive for resistant strains, and 40 percent of 20 infants who got the single dose had resistant strains. However, researchers say, the clinical significance of mutations that are not detected by standard testing remains unclear.

The infants in this trial were infected with HIV subtype C, but previous studies have shown that the six-week regimen increases resistance in infants who get infected with other HIV subtypes as well.

Despite the risk of HIV transmission, breast-feeding for at least six months is widely encouraged by the World Health Organization (WHO) and other organizations as a proven factor in better infant survival. In 2007 alone, 420,000 infants acquired HIV in utero, during birth or during breast-feeding, according to WHO estimates. HIV infection is estimated to occur in 1 out of 10 breast-fed infants, with many of the infections occurring in the first six to 14 weeks of life.

New book covers full spectrum of neuro-AIDS disorders

Tue, 09 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) In the decade-plus since the introduction of highly active antiretroviral therapy (HAART) for HIV infection, doctors have come to understand that the brain can serve as a reservoir for resistant virus, where it causes a whole different set of symptoms scientists call neuro-AIDS. A new book from ASM Press, The Spectrum of Neuro-AIDS Disorders: Pathophysiology, Diagnosis, and Treatment, presents the full scope of research on the neurological and neurobehavioral implications of HIV/AIDS in a single, unique volume.

This book represents a compendium of knowledge that is unique to the field of neuro-AIDS. At this point in the era of highly active antiretroviral therapy (HAART), we have come to appreciate, more than ever before, the implications of the brain as an organ that becomes a reservoir for resistant HIV, contributing to a deleterious impact of this chronic infection on patient functioning. The book is designed to present a coordinated focus on the integration of knowledge regarding the pathophysiological bases, diagnostic approaches, and clinical treatment strategies specific for neuro-AIDS conditions in the HAART era today, says Karl Goodkin of Cedars-Sinai Medical Center and the University of California-Los Angeles who co-edited the book with Paul Shapshak of the University of South Florida College of Medicine and Ashok Verma of the University of Miami Miller School of Medicine.

In this book, noted researchers from all over the world examine the wide range of HIV-associated neurological and neurobehavioral disorders. Neuro-AIDS can affect the entire neuraxis, resulting in physiological, neurological, and neurobehavioral deficits ranging from distal sensory polyneuropathy and primary CNS lymphoma to HIV-associated neurocognitive impairment and disorders including HIV-associated dementia. Toxicities of the antiretroviral medications themselves are a serious concern.

This book presents the wide variety of HIV-associated disorders and comorbidities with a look at the pre-HAART literature as well as the latest findings from the post-HAART era. Pathophysiology and selected neuroimaging techniques for diagnosis and assessment are examined in detail. In addition, this volume stands out for its chapters on specific patient populations such as women, children, minorities, and older persons, as well as special chapters addressing medico-legal and end-of-life concerns. The book concludes with a look at global issues and the future of neuro-AIDS in the HAART era.

While the literature in this area advances rapidly, we hope that this volume will retain its appeal over time by its structured approach to the epistemology of neuro-AIDS knowledge. We anticipate that this presentation of the conceptual underpinnings of the neuro-AIDS field will allow new data to continue to be added to the organizational tree of knowledge, resulting in a timeless value for its readers, says Goodkin.

Individuals with HIV have higher risk of non-AIDS cancers

Tue, 18 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) WASHINGTON, D.C. - The risk of non-AIDS cancer is higher for individuals infected with HIV than for the general population, according to a meta-analysis presented here at the American Association for Cancer Research's Seventh Annual International Conference on Frontiers in Cancer Prevention Research.

Compared with the general population, the risk for non-AIDS cancers was 2.3 times higher for men with HIV and 1.5 times greater for women with HIV. Among individuals with HIV, however, incidence rates were similar for those with AIDS and those without, relative to the general population.

Although the researchers did not examine why non-AIDS cancers may occur at a greater rate among individuals with HIV, clinicians should be aware of this potential increased risk when examining patients with HIV, said Meredith Shiels, M.H.S., an epidemiologist at Johns Hopkins School of Public Health.

In particular, clinicians of HIV-infected patients should inquire about well-known modifiable cancer risk factors, she said. For example, the prevalence of cigarette smoking, which is a cause of many types of cancer, is known to be higher among HIV-infected individuals.

Modern drug therapy has led to a longer life for patients with HIV. Because cancer risk increases with age, investigating the risk of cancer among patients with HIV is important. Although some cancers are known to be associated with HIV, such as Kaposi's sarcoma, non-Hodgkin's lymphoma and cervical cancer, limited research has been conducted on risk of non-AIDS cancers.

Shiels and her colleagues analyzed data from 11 U.S. and international studies comparing cancer incidence in individuals with HIV with the general population. Individual studies were excluded if they included data that overlapped with more recent studies. The meta-analysis combined standardized incidence ratios from each study and examined whether they differed by gender and prior AIDS diagnosis.

We observed an overall elevated risk for all non-AIDS cancers combined among HIV-infected individuals compared with the general population, Shiels said. The elevated risk appears to be greater among men than women.

Relative to the general population, the incidence of non-AIDS cancer appeared higher for individuals with and without an AIDS diagnosis. When the researchers adjusted the data for gender and study design, the estimates were similar: the risk of non-AIDS cancer was about two times greater than the general population for HIV-infected individuals both with and without AIDS.

When managing patients with HIV, clinicians should be aware of the potential for increased risk of non-AIDS related cancers. It is important for regular cancer screening to take place and for clinicians to encourage patients to modify factors that could affect cancer risk, such as cigarette use and nutrition.

The meta-analysis did not investigate possible reasons for the increased risk of non-AIDS cancers among patients with HIV. Understanding the link may lead to better management of cancer among patients with HIV and could be a topic for future study.

Key protein found that helps HIV assault brain

Sun, 16 Nov 2008 15:26:04 PST

( from http://www.rxpgnews.com ) Washington, Nov 15 - Researchers have isolated a key protein that explains why antiviral drugs can fend off the HIV in the body, but not in the brain.

The new study traces how key steps taken by Tat, a protein that helps HIV operate, replicate and infect cells, enables HIV to attack the brain, bringing about severe inflammation.

Researchers identified the receptor that Tat uses to attack neurons, whose effects they reversed by blocking the receptor.

'Suddenly the brain environment turns from nurturing to toxic. Cells are on overdrive, spending a lot more energy to do the same things they used to do easily,' said Harris Gelbard, neurologist at Rochester University Medical Centre.

'The current medications give many patients a new lease on life. But the virus is still taking a toll on the brain, even when the virus appears to be much less active elsewhere in the body,' said Gelbard, the paper's co-author.

The discovery of a major molecular player in the process opens up new ways of exploring how to prevent or treat HIV's neurological effects, for which there is no currently approved treatment, said a Rochester release.

Much of the molecular action that underlies HIV's attack on the brain also occurs in other diseases, such as Parkinson's and Alzheimer's diseases, and the results spell progress for those conditions as well.

The powerful antiviral drugs that keep many HIV patients healthy for years don't completely eradicate the virus from the body, and in the brain, even the very low levels of that remain cause relentless damage.

Scientists have observed that a large percentage of HIV patients - perhaps up to half - show evidence of neurologic disease from the virus.

These findings were published online in the Nov 13 issue of PloS One.

Familes fear HIV transmission if parent is infected

Tue, 11 Nov 2008 14:47:23 PST

( from http://www.rxpgnews.com ) Washington, Nov 6 - Two-thirds of families with an HIV-infected parent experienced fears about the virus spreading at home, according to a joint study.

The qualitative study is the first to interview multiple family members, including minor children, in families with an HIV-infected parent.

'We found that many of the worries were based on misconceptions about how HIV is spread,' said study co-author Burt Cowgill, staff researcher at the University of California Los Angeles -/RAND Centre for Adolescent Health Promotion.

'We also learned that HIV-infected parents had legitimate concerns about contracting infections such as a cold, flu or chicken pox while caring for a sick child,' added Cowgill.

'This knowledge could help paediatricians to address children's specific fears about HIV transmission as well as help clinicians who care for the HIV-infected parents.'

Between March 2004 and March 2005, the team conducted interviews with 33 HIV-infected parents, 27 of their children aged nine to 17, nineteen adult children and 15 caregivers -.

All HIV-infected parents had previously participated in RAND's HIV Cost and Services Utilisation Study, a national probability sample of people over 18 with known HIV infection, according to a UCLA release.

Interview questions were open-ended and broad to elicit a detailed description of family members' experiences. In addition, follow-up questions focused on whether respondents' fears subsided over time and what was done in the household to address them.

In a majority of the families, participants reported HIV transmission-related fears in the household. Concerns included acquiring HIV through contact with blood from a parent's cut, through saliva by sharing a bathroom or kissing, or by sharing food or beverages.

HIV-infected parents were also concerned about catching an opportunistic infection from a sick child or other family member, and they were especially concerned about caring for a child with chicken pox, a cold or the flu.

'Fears about disease may substantially affect the relationship between the HIV-infected parent and child,' said co-author Mark Schuster, chief of general paediatrics at Children's Hospital Boston and professor of paediatrics at Harvard Medical School.

'It is critical not only to provide children with age-appropriate information on how the disease is transmitted, but also to clear up any misconceptions.'

The findings are scheduled for publication in a forthcoming issue of Paediatrics.

Herpes drug inhibits HIV replication

Tue, 11 Nov 2008 13:55:19 PST

( from http://www.rxpgnews.com ) Washington, Nov 7 - Anti-herpes drug acyclovir can slow down HIV infection by targeting an enzyme, but is also instrumental in the emergence of multi-drug resistant HIV variants.

HIV and herpes - are two of the most common sexually transmitted diseases worldwide, and individuals frequently become infected with both.

In such cases, the two viruses interact with each other; the presence of HIV often results in more frequent HSV lesion outbreaks, while HSV can speed up the progression of HIV to AIDS.

Considering their interaction, recent studies showing that acyclovir treatment could reduce HIV viral load in co-infected patients were not surprising, and attributed to an indirect effect of HSV suppression.

However, Moira McMahon and colleagues at Johns Hopkins decided to look whether the effects on HIV might be direct.

They used a sensitive infection assay of white blood cells and found that acyclovir can directly inhibit HIV replication, the medical school said in a statement. The drug specifically targeted RT, the key HIV enzyme that converts the virus' RNA into DNA so it can be replicated.

However, acyclovir treatment had some unexpected results; five days after initial infection, a mutant version of HIV - appeared in the cells, and within 94 days spread to comprise over 90 percent of the viral population.

The V75I strain is part of the resistance pathway to many drugs, including the commonly used RT inhibitors. What this means, the authors note, is that acyclovir could be a great model for designing future HIV treatments, but also could be a risky drug if given to HSV patients co-infected with HIV by potentially promoting cross-resistance to current treatments.

These findings appeared in Journal of Biological Chemistry online Friday.

New hope for HIV treatment: Cells exhausted from fighting HIV infection can be revitalized

Mon, 10 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of Toronto and the University of California, San Francisco, have revealed new hope for HIV treatment with the discovery of a way to 'rescue' immune cells that are exhausted from fighting off HIV infection.

The team lead by Drs. Mario Ostrowski, of the University of Toronto's Faculty of Medicine, and Douglas Nixon, of the Division of Experimental Medicine at the University of California, San Francisco, has discovered that a molecule called Tim-3 is present at high levels on poorly functional immune system cells which are 'exhausted' from fighting HIV infection. The researchers found that blocking the activity of Tim-3 on these cells improved their function and allowed them to rejoin the battle against HIV.

In the typical course of HIV infection, an initial burst of very high levels of the HIV virus is brought partially under control by the infected person's immune system, specifically by an immune system cell called a CD8+ killer T cell. In the majority of cases without antiretroviral drug treatment, the immune system is eventually overwhelmed and progression to AIDS occurs, said co-principal author Brad Jones, a PhD candidate in Immunology at the University of Toronto.

Progression to AIDS is associated with a breakdown in those CD8+ T immune system cells. In a typical viral infection, those cells rapidly multiply, kill off virus-infected cells and stimulate other cells in the immune system. But over time, in the battle to fight off HIV infection these CD8+T cells become less functional and enter into a state known as 'exhaustion.' The mechanisms that lead to this exhausted state are not well known, said Jones. We felt that if we could understand these mechanisms then we may be able to intervene and re-energize the immune system. The research team theorized that this exhausted state may result from the Tim-3 molecule sending a signal to shut down CD8+ T cells in HIV-infected individuals.

The researchers observed that Tim-3 expression on T cells, in particular the CD8+ T cells, associated remarkably strongly with clinical parameters of HIV disease progression in a diverse group of HIV-infected individuals. From these results we predicted that the Tim-3 pathway might be manipulated to potentially confer clinical benefit and serve as a promising new target for clinical intervention to decrease the severity of HIV infection, said co-principal author Lishomwa Ndhlovu, MD, PhD in the Division of Experimental Medicine, University of California, San Francisco.

To test this, we produced a molecule capable of blocking the Tim-3 signal and studied the effect that this had on CD8+ T cell function in vitro, said Mario Ostrowski, MD, Associate Professor in the Department of Immunology, University of Toronto. We observed that blocking the Tim-3 pathway rescued those cells and restored their ability to fight off infection.

This discovery, published in the November 24th issue of the

Panel advocates improved understanding of hepatitis B and screening of high-risk populations

Thu, 23 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Management of hepatitis B is a challenge for physicians and patients due to an incomplete understanding of the disease course, complex treatment indications, and the lack of large studies focusing on important health outcomes. To examine these issues, the NIH convened an independent, impartial panel this week to weigh the available evidence on the management of hepatitis B.

While more than 95 percent of U.S. children are routinely vaccinated for hepatitis B, the vaccine does not protect individuals already infected with the virus. In unprotected individuals, acute infection with the hepatitis B virus is usually resolved by the body's immune system and does not cause long-term problems. The transition from acute to chronic infection appears to occur when the immune system does not effectively destroy and clear virus-infected cells.

A number of antiviral therapies approved by the U.S. Food and Drug Administration are available for use in fighting chronic hepatitis B infection including interferons and nucleos(t)ides. We know that these therapies have positive effects on indicators such as viral load, but further controlled trials are needed to substantiate that these agents prevent disease progression to liver failure, cancer, or death, explained panel chair Dr. Michael F. Sorrell, Professor of Medicine at the University of Nebraska Medical Center.

To address this gap in the evidence, the panel recommended several avenues for future research. Among these, they gave top priority to large andomized studies, including placebo-controlled trials, testing single drug and combination therapies' effects on liver failure, cancer, and death. The panel also proposed representative prospective cohort studies to define the natural history of the disease to optimize management across diverse patient subgroups. This would also help decide which patients are most in need of immediate therapy and which could be carefully followed without drug therapy.

The panel is encouraged by the National Institute of Diabetes and Digestive and Kidney Disorders' plans to launch the Hepatitis B Clinical Research Network to promote translational research on this challenging condition. It is anticipated that the recommendations in the consensus statement will inform the consortium's research agenda.

The panel identified elevated hepatitis B DNA blood levels and elevated levels of ALT (alanine aminotransferase, a liver enzyme) as the most important indicators for progression to cirrhosis and liver cancer (hepatocellular carcinoma). Older age, male sex, family history of liver cancer, coinfection with hepatitis C or HIV, and elevated blood levels of hepatitis B DNA were also found to be key predictors.

The panel recommends routine hepatitis B screening for newly arrived immigrants from countries where hepatitis B prevalence is greater than two percent. These practices are intended to facilitate access to care for infected individuals and their families and to provide valuable data on disease prevalence, not to exclude immigrants in any way.

The panel recommends therapy for certain patients, including those with acute liver failure and complications from cirrhosis. However, immediate therapy is not indicated for patients with inactive forms of the disease.

The panel's complete consensus statement will be available later today at

Integrating antiretroviral therapy with TB treatment for co-infections reduces mortality

Thu, 16 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) October 16, 2008 -- A South African treatment study conducted by researchers in the Department of Epidemiology at the Mailman School of Public Health shows that mortality among TB-HIV co-infected patients can be reduced by a remarkable 55%, if antiretroviral therapy (ART) is provided with TB treatment at the same time. The randomized, known as the SAPIT (Starting Antiretrovirals at three Points in Tuberculosis) trial, randomly assigned TB-HIV co-infected patients to receive ART. Patients who received ART together with their TB treatment (integrated treatment arm) were compared with patients assigned to receive ART upon completion of TB treatment (sequential treatment arm).

The study shows that integrating TB and HIV treatment and care saves lives, says Salim S. Abdool Karim, MD, PhD, professor of clinical Epidemiology at the Mailman School of Public Health and director of the Centre for the AIDS Program of Research in South Africa (CAPRISA), who led the SAPIT trial. The trial was conducted at the CAPRISA eThekwini TB-HIV Clinic which is attached to the largest TB clinic in Durban, South Africa. The study was initiated in June 2005 and completed enrollment of 645 patients with TB and HIV co-infection in July 2008. It is estimated that about 70% of all TB patients in South Africa are infected with HIV, or about 250,000 of the 353,879 TB patients diagnosed in 2007.

As a result of the higher mortality rate in patients in the sequential treatment arm versus the mortality rate for those patients in the integrated treatment arm, the study's independent Safety Monitoring Committee recommended in their review of the trial in September 2008 that the sequential arm of the trial be stopped and that ART be initiated in this group as soon as possible. The Committee further recommended that the two sub-groups within the integrated treatment arm (early TB-HIV treatment and post-intensive phase TB-HIV treatment) should continue as per protocol.

Dr. Peter Piot, executive director of UNAIDS, commented: These important results show that a ''two diseases, one patient, one response integrated approach to TB/HIV treatment avoids unnecessary deaths from TB, the leading cause of death in people living with HIV in Africa. TB is the most common disease occurring in the late stages of HIV infection in southern Africa. As a result, many people throughout southern Africa are first identified as HIV infected when they develop TB. The findings of the SAPIT study call for the accelerated implementation of routine HIV testing in TB treatment services.

The SAPIT trial results provide compelling evidence to support the World Health Organization's call for the greater collaboration between TB and HIV treatment services and provide empiric evidence of the benefits from the initiation of antiretroviral therapy in TB-HIV co-infected patients. Dr Paul Nunn, of the Stop TB Department at the World Health Organization commented, The results to date clearly show the urgent necessity to make ART available to HIV infected patients with TB worldwide. In South Africa alone, it would result in an additional 100,000 to 150,000 TB patients being initiated on ART resulting in about 10,000 deaths being averted each year.

Ambassador Mark Dybul, Coordinator of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) said: Scaling up collaborative TB/HIV activities is a priority for PEPFAR. We remain committed to increasing screening for both HIV and TB, which will allow greater numbers of patients to benefit from these study results.

HIV drug maraviroc effective for drug-resistant patients

Wed, 01 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Oct. 2, 2008) -- As many as one quarter of HIV patients have drug resistance, limiting their treatment options and raising their risk for AIDS and death. Now, maraviroc, the first of a new class of HIV drugs called CCR5 receptor antagonists, has been shown to be effective over 48 weeks for drug-resistant patients with R5 HIV-1, a variation of the virus found in more than half of HIV-infected patients.

Results of the two Phase 3 multicenter MOTIVATE (Maraviroc Plus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients) studies led by NewYork-Presbyterian Hospital/Weill Cornell Medical Center's Dr. Roy Gulick and published in the October 2 issue of the New England Journal of Medicine (NEJM) find that the drug, taken with an optimized standard HIV drug regimen, resulted in significantly greater suppression of the virus at 48 weeks, with concurrent increases in immune system T-cell counts, when compared with placebo. Rates of side effects were not different between the maraviroc and placebo groups.

Preliminary results of these studies led to FDA approval of maraviroc in August 2007.

Because it is from a new class of HIV medications known as HIV entry inhibitors, people living with HIV generally will not have resistance to maraviroc because they have not been exposed to any drugs from the class previously. Unlike earlier HIV drugs that target the virus, maraviroc acts on the human T-cell, binding to it in such a way that prevents HIV from binding and subsequently infecting the T-cell.

It is now possible to expect that a majority of treatment-experienced patients who experience failure on their current HIV drugs will regain control of their HIV infection with maraviroc combined with other newer antiretroviral drugs. This is an important step forward, says study principal investigator Dr. Roy Gulick, who is professor of medicine and director of the Cornell HIV Clinical Trials Unit of the Division of International Medicine and Infectious Diseases at Weill Cornell Medical College, and a practicing physician at NewYork-Presbyterian Hospital in New York City. Suppressing virus levels and increasing immune system T-cells with HIV treatment regimens helps HIV-infected people live longer, healthier lives.

The double-blind study followed 1,049 of patients with advanced HIV and resistance to three antiretroviral drug classes. Patients were randomized to receive maraviroc once-daily, twice-daily or placebo. Safety and efficacy were assessed at 48 weeks. The MOTIVATE studies comprised two identical arms: MOTIVATE1 was conducted in Canada and the U.S., while MOTIVATE2 was conducted in Australia, Europe and the U.S.

UNC receives record $181 million grant to evaluate health, poverty and gender programs worldwide

Mon, 08 Sep 2008 03:59:37 PST

( from http://www.rxpgnews.com ) The United States Agency for International Development (USAID) has awarded the Carolina Population Center at the University of North Carolina at Chapel Hill up to $181 million to continue its MEASURE Evaluation project.

The award is the largest ever received by UNC.

The award funds the monitoring and evaluation of family planning, maternal and child health, nutrition and HIV/AIDS programs around the world. The project also monitors and evaluates malaria, tuberculosis and avian influenza programs, and will expand to programs addressing poverty and gender equity.

Going into its third phase, MEASURE Evaluation builds on the previous two phases of the project and the earlier EVALUATION project which began in 1991. The project already has a presence in nearly 50 countries in Africa, Asia, Europe and Latin America and will expand to more. Besides the $181 million of project funding in this grant, the award includes the potential for countries to request evaluation activities valued at up to an additional $125 million over the five years.

The size of this award is unprecedented, said Barbara Entwisle, Ph.D., director of the Carolina Population Center (CPC) and Kenan Professor of Sociology in the UNC College of Arts and Sciences. Faculty at UNC, specifically those at the Carolina Population Center who are part of the MEASURE Evaluation team, have achieved an international reputation for excellence in evaluation research.

The funding of this latest stage of the project acknowledges the great success of the MEASURE Evaluation team in its earlier phases.

Sian Curtis, Ph.D., research associate professor of maternal and child health in the School of Public Health and a CPC fellow, is principal investigator and project director. Gustavo Angeles, Ph.D., assistant professor of maternal and child health in the School of Public Health and CPC fellow, is co-principal investigator and deputy director.

Good information is essential to improve the health of the world's population, Curtis said. This award provides a fabulous opportunity to strengthen our understanding of global health programs and improve the collection, analysis and use of population and health information.

The project's partners includes John Snow Inc., Macro International, Tulane University, The Futures Group International and Management Sciences for Health.

The MEASURE (Monitoring and Evaluation to Assess and Use Results) Evaluation project uses different strategies to collect and use data about health issues. For example, a tool for assessing and modifying HIV/AIDS prevention programs locally or nationally called the Priorities for Local AIDS Efforts (PLACE) method can identify geographic areas that contain key HIV transmission networks. The PLACE method was developed by Sharon Weir, Ph.D., research assistant professor of epidemiology in the School of Public Health and a CPC fellow.

The project will focus on developing the expertise of health workers and officials in host countries to collect, analyze and use data that are gathered. Building on its existing monitoring and evaluation training courses, researchers will launch a distance learning component to increase the number of people who are trained to monitor and evaluate health programs. Communities of practice will also be created so people from different countries who work on the same health issue can share information and learn from each other.

Combination HIV prevention can avert 12 million cases by 2015

Wed, 06 Aug 2008 11:02:28 PST

( from http://www.rxpgnews.com ) London, Aug 6 - Combination HIV prevention, if thoroughly implemented by governments and communities, can avert 12 million infections by 2015, according to experts. Right now, some 7,000 people are infected daily around the world.

A report authored by Peter Piot and Michael Bartos of the joint United Nations Programme on HIV/AIDS, Geneva said a quarter century of AIDS responses has created vast knowledge about HIV transmission and prevention, yet some 7,000 people are infected daily worldwide.

'If combination prevention is intensified as rapidly as possible from today, then some 12 million fewer HIV infections will occur if incidence at today's levels remains constant, and the annual number of new infections in 2015 will have reduced by two-thirds.'

Essential programmes have not had sufficient funding or coverage, and such programmes have often not been targeted to the populations that need them most.

The authors called for confident and unified leadership to overcome the political, cultural, and logistic barriers to effective HIV prevention.

This includes mustering support for proven interventions such as the frank education of young people, harm reduction policies for injecting drug use, and including sexual minorities in HIV programmes.

International institutions, national governments and community activists must work together to build demand for HIV prevention. Support must be rallied in every area possible, including workplaces, schools, communities and places of worship.

An active coalition between the movement for HIV prevention and the movement of people living with HIV/AIDS should also be created and linked with other social movements such as treatment activists, entrepreneurs, and women's and youth activists.

The authors urged scientists, research bankrollers and programme planners to broaden the HIV-prevention research agenda, in particular through a greater focus on operational research to help guide optimum programme scale-up.

The report appeared in British medical journal The Lancet.

HIV expert says 1 step down, 2 more to go in quest to cure AIDS

Wed, 06 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A Johns Hopkins expert in HIV and how the AIDS virus hides in the body says antiretroviral drugs have stopped HIV from replicating, the first of three key steps needed to rid people of the virus.

In an address to be delivered Aug. 6 at the XVII International Conference on AIDS, taking place in Mexico City, infectious disease specialist Robert Siliciano, M.D., Ph.D., says current drug-combination therapies can stop HIV in its tracks, with some combos suppressing its ability to make copies to less than one in a billion.

But, he says, progress is still needed in identifying where viral reservoirs persist and in finding ways to eliminate these HIV hiding places.

Indeed, it was Siliciano's team at Hopkins in 1995 that confirmed the existence of these reservoirs in immune system CD4 memory T-cells - those left behind, after an initial infection, to fight recurrences. The CD4s concentrate in the lymph nodes and spleen. Siliciano suggests that other as yet unverified viral pools could exist, citing previous studies at Johns Hopkins that, in 2006, identified adult stem cells and progenitor cells as potential hideaways for HIV.

According to Siliciano, a professor at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator, laboratory models that mimic HIV infection in these reservoir cells are key to finding drugs that can eliminate them.

We know now that HIV can be stopped, says Siliciano. Our next steps are to go after these reservoirs of HIV. And although much work needs to be done to find and eliminate them, infected people who have access to antiretroviral drugs and who take them as prescribed stand a good chance of leading normal lives.

Siliciano points out that if antiretroviral drugs can be made more accessible, affordable and less toxic, then infected people who take the drugs correctly will not develop AIDS.

Included in Siliciano's presentation are recent data from his team and researchers at the National Cancer Institute and the University of Pittsburgh, which shows that adding a fourth, more potent anti-HIV drug to existing antiviral combinations does not further suppress the number of HIV viral copies in the blood.

Adding more drugs to current regimens will not further reduce the amount of virus in the blood, says Siliciano. We have already reached rock bottom in using drugs to stop HIV from replicating. The trace amounts of virus that remain are coming from viral reservoirs, not active replication of the virus.

In 15 HIV-positive study participants already using highly active antiretroviral therapy, or HAART, to suppress the virus, researchers added either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. They found no greater suppression in viral blood levels than seen before the fourth drug was added.

Hundreds of thousands of the more than 1 million Americans infected with HIV are currently using HAART, a combination usually of three of 25 potent antiviral medications. And these drugs almost eliminate the amount of virus in the blood, lowering the number to fewer than 50 copies per cubic milliliter of blood.

Siliciano also describes the progress of four laboratory models for testing HIV reservoirs, including one developed at Johns Hopkins, in identifying all viral reservoirs, and in penetrating them with antiretroviral drugs.

There are more than 33 million people in the world living with HIV, including an estimated 950,000 in the United States and 23,000 in the state of Maryland.

Stanford study finds HIV drug can persist in mothers' milk, increasing risk to them and their babies

Tue, 05 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) STANFORD, Calif. - A drug commonly used in the developing world to prevent transmission of HIV from mother to child persists in the breast milk and blood of the mothers, putting them and their babies at risk for developing drug-resistant strains of the virus, according to researchers at the Stanford University School of Medicine.

The researchers found that the drug, nevirapine, stays in the blood and breast milk of the infected mothers for at least two weeks. During that time, the virus has ample opportunity to transform itself into drug-resistant strains of HIV, the human immunodeficiency virus that causes AIDS, which can be very difficult to treat.

In the short term, nevirapine is better than nothing, said David Katzenstein, MD, professor of infectious diseases and principal investigator of the study. But in the long term, I'm concerned about conferring resistance. If you're talking about resistance on a broad scale, it could jeopardize future treatment for mothers and infants.

Seble Kassaye, MD, instructor in infectious diseases and first author of the study, will present the results Aug. 5 at the International AIDS Conference in Mexico City.

Last year, 420,000 babies were born HIV-positive, the large majority of them to HIV-infected mothers in sub-Saharan Africa, according to figures from the United Nations Joint Programme on HIV/AIDS. The centerpiece of public health programs in the developing world to stop mother-to-child transmission of HIV are both zidovudine (AZT) and nevirapine, which have been used as preventive tools in nearly 900,000 women and infants worldwide. The drugs are relatively inexpensive and easy to administer, and nevirapine is typically given as a single pill as the mother goes into labor and as a liquid to the baby just after birth. Use of the drug reduces the chance of HIV transmission by half, to about 13 percent. However, not all HIV-infected women have access to one or both of these drugs, especially in sub-Saharan Africa.

In addition, nevirapine has proven to be problematic. Previous studies have found that as many as 69 percent of HIV-positive mothers and as many as 80 percent of babies born infected, even after being given a single-dose of nevirapine without AZT, may develop nevirapine-resistant strains of the virus.

In the latest study, the Stanford scientists set out to better understand this problem.

They looked at a group of 32 HIV-positive pregnant women in Zimbabwe, where Katzenstein and his colleagues have had ongoing research and clinical programs in HIV/AIDS for more than a decade. The sub-Saharan African country has been hard hit by the virus, with an estimated 17 to 18 percent of young adults estimated to be infected. Among pregnant women, some 20 percent are thought to carry the virus.

In recent years, Zimbabwe has begun offering antiretroviral drugs to a limited number of infected patients, but at the time of the study, none of the women had been treated for their HIV. The only drug they received was the single dose of nevirapine when they went into labor, largely for the sake of their babies.

The researchers found that the drug persisted in the body for weeks, with more than half of the women having detectable levels in their blood within two weeks after delivery. Two-thirds had measurable levels in their breast milk at two weeks, the researchers found.

The longer the drug remains in the system, the more likely it is to promote development of mutations in the virus. Although none of the HIV-infected women carried drug-resistant strains of the virus at the outset of the study, at two months after birth RNA tests showed a third of them had drug-resistant virus in their blood. Sixty-five percent had drug-resistant strains in their breast milk as well, with the potential to pass this on to their babies through breastfeeding, a common mode of viral transmission.

The mothers who were most likely to develop resistant virus were those whose disease was more advanced as indicated by lower CD4 cell counts, the immune cells targeted by HIV, Kassaye said. With advanced HIV infection, these women are likely have more replicating virus, so they may be more prone to developing mutations that make the virus resistant to treatment, she said.

If these women had access to better, combination antiretroviral treatment to optimally suppress virus replication, they might be less likely to develop these hard-to-treat strains later, she said.

It reinforces the need to treat these women with combination therapy, thereby providing better prevention for the infant, while providing better treatment for the mother, Kassaye said. Public health efforts should continue to expand combination therapy so that mothers and babies aren't left vulnerable to drug resistance.

Combination therapy is a mix of drugs that is more expensive - and thus less accessible - in the developing world. In the United States, HIV-positive women receive a highly effective form of combination therapy that has reduced transmission of HIV from mother to infants to less than 2 percent.

Group of HIV patients with inadequate care

Mon, 04 Aug 2008 13:59:44 PST

( from http://www.rxpgnews.com ) Doctors who treat HIV-infected crack users refer to them as "the forgotten population." A study being presented at this week's International AIDS Conference in Mexico City reveals that these patients frequently lack outpatient health care, do not receive life-saving antiretroviral therapy and continue to engage in risky sexual behavior that likely contributes to HIV transmission.

Researchers interviewed 190 HIV-infected crack-using patients at Grady Memorial Hospital in Atlanta and Jackson Memorial Hospital in Miami over 14 months as part of an NIH/National Institute on Drug Abuse funded study.

One fourth of the group reported having unprotected sex in the last six months, half had not seen an HIV specialist in the last six months, and more than three fourths were not getting antiretroviral therapy, according to the interviews.

The five-year HOPE study (Hospital visit is an Opportunity for Prevention and Engagement) is a collaboration between the NIH funded Center for AIDS Research at Emory University School of Medicine and the NIH funded Developmental Center for AIDS Research at the University of Miami School of Medicine.

"At a time when life-saving medications are available to treat persons living with HIV, there continues to be a population of HIV-positive people who have fallen through the cracks," says Lisa Metsch, PhD, associate professor of epidemiology and public health at University of Miami School of Medicine. "Frequently, their only contact with the healthcare system is during a hospitalization."

Metsch is director of the University of Miami CFAR's behavior, social sciences and community outreach core and principal investigator for the HOPE study.

Previous studies of crack users in urban hospitals found that their drug use bars them from getting HIV-related care. Drug treatment experts say the short, intense nature of the crack high and lack of a methadone equivalent make crack users a unique group, on top of the chaotic lives they share with other drug users.

In addition, the study's interviews found that, compared with males, female HIV-infected crack users were more likely to report lack of HIV-related care (almost twice as likely) and recent unprotected sex (three times as likely), as well as annual income less than $5,000 and homelessness.

"We know that not being engaged in care and prevention services is not only bad for the individuals but is also bad for society, in that a substantial fraction of HIV-infected crack users engage in behavior that transmits the virus to others," says Carlos Del Rio, MD, professor of medicine and chief of medical services at Grady Memorial Hospital, co-director of the Emory Center for AIDS Research and co-principal investigator for the HOPE study.

The Emory and University of Miami researchers are testing the effectiveness of an eight-session intervention program that helps participants get into HIV care, teaches them about reducing risky sex practices and helps them into drug treatment if they are ready.

Del Rio says that the findings from this intervention study may be used to establish future interventions targeted to HIV-infected crack users to get them into care, keep them in care and allow them to benefit from care and prevention services available in HIV outpatient clinics.

"Hospitals like Grady and Jackson are doing the best they can in the face of a persistent problem, with limited resources," Del Rio says. "More needs to be done to address substance abuse and mental health in this population."

Antiretrovirals do not increase the risk for coronary atherosclerosis

Mon, 04 Aug 2008 13:07:25 PST

( from http://www.rxpgnews.com ) Antiretroviral drugs for HIV do not increase the risk for coronary atherosclerosis, a central risk factor for heart disease, according to a study led by the University of Pittsburgh Graduate School of Public Health to be published in the Aug. 8 issue of the journal AIDS and available online today. The results further suggest that antiretroviral therapy may offer men with HIV some protection against atherosclerosis – hardening of the arteries, caused in part by high levels of cholesterol, smoking and other lifestyle factors.

The study, part of the Multicenter AIDS Cohort Study (MACS) initiated in 1983, measured levels of coronary artery calcification (CAC) in nearly 950 HIV-positive and HIV-negative men by CT scanning completed between 2004 and 2006. Controlling for traditional atherosclerosis risk factors such as age, family history, smoking and blood pressure, the study team found that CAC scores were almost 60 percent lower in HIV-positive men who received highly active antiretroviral therapy (HAART) for more than eight years compared to HIV-negative men.

HAART, a course of treatment that involves the combination of three or more antiretrovirals, has been associated with an increase in cholesterol and other factors associated with atherosclerosis, leading some to question whether long-term use increases the risk of heart attack.

"When we first prescribed highly active antiretroviral therapy for HIV in 1995, we were concerned about how these drugs changed lipid levels in patients and whether they would increase atherosclerosis and ultimately lead to serious heart disease," said Lawrence Kingsley, Ph.D., study lead author and associate professor, Departments of Infectious Diseases and Microbiology and Epidemiology, University of Pittsburgh Graduate School of Public Health. "While some studies have found an association between these antiretroviral treatments and increased risk of cardiovascular disease, we believe our findings should reassure clinicians that using antiretroviral therapy over time does not appear to put patients at greater risk for coronary atherosclerosis and may, in fact, be more beneficial than we had initially thought."

The study also found that for both HIV-positive and HIV-negative men, older age was most strongly associated with the presence of coronary atherosclerosis. Smoking, lipid abnormalities and family history also played a role.

"This was not surprising since these are the major risk factors for atherosclerosis in the general population," said Dr. Kingsley. "The purpose of our study, however, was to investigate whether long-term HAART usage was a major risk factor."

"These results could be due, in part, to lower lipid values of HIV infected men prior to beginning antiretroviral therapy and high use of lipid-lowering drugs. The key is that controlling risk factors for atherosclerosis should be a priority," added Lewis Kuller, M.D., Dr.P.H, study co-author and professor of epidemiology, University of Pittsburgh Graduate School of Public Health.

Dr. Kingsley concluded, "What remains to be determined is whether use of the newest antiretroviral therapies confers an even better outcome and whether lipid-lowering therapies will further improve cardiovascular risk in the HIV-infected population. Our future research will address these questions."

Study highlights risky behavior, lack of care among HIV-infected crack users

Mon, 04 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Doctors who treat HIV-infected crack users refer to them as the forgotten population. A study being presented at this week's International AIDS Conference in Mexico City reveals that these patients frequently lack outpatient health care, do not receive life-saving antiretroviral therapy and continue to engage in risky sexual behavior that likely contributes to HIV transmission.

Researchers interviewed 190 HIV-infected crack-using patients at Grady Memorial Hospital in Atlanta and Jackson Memorial Hospital in Miami over 14 months as part of an NIH/National Institute on Drug Abuse funded study.

One fourth of the group reported having unprotected sex in the last six months, half had not seen an HIV specialist in the last six months, and more than three fourths were not getting antiretroviral therapy, according to the interviews.

The five-year HOPE study (Hospital visit is an Opportunity for Prevention and Engagement) is a collaboration between the NIH funded Center for AIDS Research at Emory University School of Medicine and the NIH funded Developmental Center for AIDS Research at the University of Miami School of Medicine.

At a time when life-saving medications are available to treat persons living with HIV, there continues to be a population of HIV-positive people who have fallen through the cracks, says Lisa Metsch, PhD, associate professor of epidemiology and public health at University of Miami School of Medicine. Frequently, their only contact with the healthcare system is during a hospitalization.

Metsch is director of the University of Miami CFAR's behavior, social sciences and community outreach core and principal investigator for the HOPE study.

Previous studies of crack users in urban hospitals found that their drug use bars them from getting HIV-related care. Drug treatment experts say the short, intense nature of the crack high and lack of a methadone equivalent make crack users a unique group, on top of the chaotic lives they share with other drug users.

In addition, the study's interviews found that, compared with males, female HIV-infected crack users were more likely to report lack of HIV-related care (almost twice as likely) and recent unprotected sex (three times as likely), as well as annual income less than $5,000 and homelessness.

We know that not being engaged in care and prevention services is not only bad for the individuals but is also bad for society, in that a substantial fraction of HIV-infected crack users engage in behavior that transmits the virus to others, says Carlos Del Rio, MD, professor of medicine and chief of medical services at Grady Memorial Hospital, co-director of the Emory Center for AIDS Research and co-principal investigator for the HOPE study.

The Emory and University of Miami researchers are testing the effectiveness of an eight-session intervention program that helps participants get into HIV care, teaches them about reducing risky sex practices and helps them into drug treatment if they are ready.

Del Rio says that the findings from this intervention study may be used to establish future interventions targeted to HIV-infected crack users to get them into care, keep them in care and allow them to benefit from care and prevention services available in HIV outpatient clinics.

Hospitals like Grady and Jackson are doing the best they can in the face of a persistent problem, with limited resources, Del Rio says. More needs to be done to address substance abuse and mental health in this population.

UGA researchers win $9.2 million stem cell grant from NIH

Mon, 04 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A research group led by Stephen Dalton, professor and Georgia Research Alliance Eminent Scholar of Molecular Biology at the University of Georgia, has been awarded $9.2 million as part of a major new research grant by the National Institute of General Medical Sciences, part of the National Institutes of Health.

Dalton's group, headquartered in the department of biochemistry and molecular biology, will address the molecular underpinnings of the early steps that stem cells take in becoming specialized cell types. The scientists will also seek to identify the genetic and protein modification patterns that accompany this process of differentiation.

The new grant in UGA's Franklin College of Arts and Sciences is part of $27 million in funding awarded to the University of Wisconsin, UCLA and UGA that NIGMS has added to its ongoing effort to uncover the basic biology of human embryonic stem cells.

Our program will offer training for scientists seeking to gain expertise in the specialized techniques needed to work with embryonic stem cells and will serve as a source of reagents, technical support and methodology development, said Dalton, who is also a Georgia Cancer Coalition Distinguished Scholar and a member of UGA's developmental biology program.

The results of all three new programs are expected to deepen existing knowledge of the unique properties of stem cells and will be important to researchers trying to develop stem-cell-based therapies.

This program project grant is important for a number of reasons, said David Lee, UGA vice president for research. Certainly it highlights the expertise in stem cell biology and glycomics at the University of Georgia. But perhaps more important, it is cleverly designed to promote stem cell research throughout the Southeast. One of the core facilities funded by the grant is specifically tasked with developing new stem cell technologies that will be disseminated to researchers across the region via the new Southeast Stem Cell Consortium, which Professor Dalton chairs. We are extremely pleased by the leadership provided by Dr. Dalton in an area that offers so much promise for human health.

Dalton's position as a leader in stem-cell research has been solidified with the recent establishment of the Southeast Stem Cell Consortium. The consortium has strong interests in the basic biology of stem cells, their utility as a model for studying mammalian development and their potential as a cell source to develop therapies for degenerative disease and repair of chronic injury. Focus areas include diabetes, cardiovascular disease, spinal cord injury and neurodegenerative disease.

This is an innovative program that focuses on an understudied area of stem cell biology, said Marion Zatz, Ph.D., who oversees stem cell grants at the National Institute of General Medical Sciences of the National Institutes of Health. By looking at how proteins are modified by sugar molecules as stem cells differentiate, Dalton's team could help us understand how the many distinct cell types in our bodies are formed.

Dalton's research group at UGA focuses on the uses of stem cells in understanding diabetes and cardiovascular disease. One current project involves finding ways to use stem cells to repair the human heart.

The heart is an organ that doesn't repair itself, said Dalton. But we're studying a resident population of stem cells that have the capability of dividing and turning into cardiac cells. Theoretically, they could be used to help the heart repair itself after a heart attack.

The new programs join an NIGMS effort launched in 2003 to explore the basic molecular and genetic features of human embryonic stem cells. Prior to the latest awards, the initiative has included six exploratory centers, two multidisciplinary research programs and several independent research projects and supplements.

New male circumcision device for HIV prevention studied by NewYork-Presbyterian/Weill Cornell

Fri, 01 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (July 31, 2008) -- With the recent endorsement by the World Health Organization (WHO) and scientists worldwide of adult male circumcision as an important strategy for HIV prevention, there is increased urgency to develop safe and cost-effective circumcision services. This is especially the case in Africa where HIV/AIDS continues to spread at an epidemic rate.

Studying this method are Dr. Marc Goldstein and physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, who are evaluating an innovative circumcision device developed in China and will initiate a study of the device in Africa in the coming months.

The device, named the ShangRing after its inventor, Mr. Jian-Zhong Shang, consists of two concentric plastic rings that sandwich the foreskin, allowing it to be cut away without suturing and with minimal bleeding. Performed in a clinic under local anesthesia, the procedure takes less than five minutes, compared with approximately 20 to 30 minutes for a traditional free hands circumcision that requires suturing. The patient returns in one week for device removal.

Circumcision with this technique promises to be faster, safer and more acceptable to patients than conventional surgical circumcision methods, says Dr. Goldstein, the study's principal investigator. He is urologist and specialist in reproductive medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, the Matthew P. Hardy Distinguished Professor of Reproductive Medicine and Urology at Weill Cornell Medical College, and senior scientist at The Population Council, Center for Biomedical Research, located on the campus of The Rockefeller University.

The hope is that with these advantages, circumcision will become more commonplace (currently only between 15 and 50 percent of sub-Saharan males are circumcised). Its advantages include reduced risk of a variety of sexually transmitted diseases (STDs), notably HIV.

Circumcision is the only new HIV prevention method to demonstrate consistent efficacy in randomized controlled trials, notes co-principal investigator Dr. Philip S. Li, associate research professor of urology and reproductive medicine and director of microsurgical research and training at the Center for Male Reproductive Medicine and Microsurgery at Weill Cornell Medical College.

Three randomized controlled trials in Kenya, Uganda and South Africa reported a protective effect (up to 60 percent) of circumcision against HIV infection. The World Health Organization, the Joint United Nations Programme on HIV/AIDS (UNAIDS), and other global reproductive health organizations such as EngenderHealth have recognized circumcision as an important method to reduce HIV infection.

The ShangRing has been used to circumcise several thousand Chinese men since 2005. Preliminary reports of 1,200 patients indicate good results with minimal complications. The ShangRing, with 15 patents pending in 85 countries, is currently available only in China. FDA evaluation is under way.

The beauty of this device is its simple, innovative design, says Dr. Howard Kim, a fellow in male reproductive medicine and microsurgery at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and member of the Weill Cornell team that traveled to China to learn this new technique. Although many male circumcision devices are available, they have not gained widespread acceptance due to high complication rates or difficulties with surgical technique.

Even non-physician health care providers will be able to learn this procedure to safely perform circumcisions in resource-poor regions, adds Dr. Richard Lee, a chief resident in urology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and another member of the China team.

The NewYork-Presbyterian/Weill Cornell team, in collaboration with the nonprofits EngenderHealth and The Population Council, are planning a small pilot study in Nyanza, Kenya, to test efficacy, safety and acceptability of the technique. Local health providers who perform circumcisions in a clinical setting will be recruited and trained in the procedure by the NewYork-Presbyterian/Weill Cornell team. The pilot study is expected to be followed by a multicenter clinical trial that will compare the ShangRing technique to traditional circumcision methods.

Male circumcision has been performed as far back as ancient Egypt, and the practice has continued through the ensuing centuries for religious, cultural and sociopolitical reasons. Performing circumcision for potential health benefits gained momentum in the 19th century with the advent of anesthesia and the initial epidemiological studies demonstrating lower rates of venereal diseases in circumcised men. Recent studies have shown that circumcised men are at significantly lower risk of urinary tract infections and sexually transmitted infections such as syphilis and chancroid. Additional studies point to lower risk of invasive penile carcinoma, gonorrhea and chlamydia (in female partners).

ASM and FIND to partner on strengthening infectious disease diagnosis in developing nations

Thu, 31 Jul 2008 03:59:37 PST

( from http://www.rxpgnews.com ) The American Society for Microbiology (ASM) and the Foundation for Innovative New Diagnostics (FIND) have signed a Memorandum of Understanding today confirming their agreement to work in partnership for projects aimed at strengthening infectious disease diagnosis and service integration in resource-poor and transitional countries.

The collaboration between the ASM and FIND will focus on strengthening the foundation for infectious disease diagnosis in resource-poor nations, providing novel diagnostics and laboratory expertise for tuberculosis and other infectious diseases that are appropriate to the unique circumstances found in developing nations, says Steven Specter, Chair of the ASM's International Laboratory Capacity Building Committee.

The memorandum of understanding signed by the ASM and FIND arises from a pilot project that the two organizations have been conducting in Cote d'Ivoire since April 2008. In the pilot collaboration, FIND is developing and providing rapid, accurate and affordable tuberculosis diagnostic tests that can be effectively deployed in resource poor areas while the ASM is sending experts in clinical microbiology to provide training and technical assistance in the implementation of these new tests.

We expect our partnership to reinforce the expansion and further development of quality-assured laboratory services as part of a larger framework of health system strengthening within resource-poor settings. Combating poverty-related infectious diseases with the development and rapid introduction of new diagnostic tests where they are most needed is why partnerships like the one between FIND and ASM are extremely important, says Giorgio Roscigno, CEO of FIND.

The WHO estimates that 2 billion people, or approximately one third of the world's population, are infected with the bacteria that cause tuberculosis. Africa represents 28% of all tuberculosis cases and has the highest infection rate per capita. Tuberculosis is a leading cause of death among people living with HIV/AIDS and most of the world's 200,000 HIV/TB deaths occur in Africa.

One of the primary challenges is that modern diagnostic tools for tuberculosis in industrialized countries are not suited to the infrastructure of resource poor nations where in some cases just getting reliable electricity is a problem. New, reliable diagnostics that can be effectively implemented in developing nations, as well as the expertise to use them, are urgently needed.

FIND is prioritizing tests that can be adopted at the lowest level of the health system, where a large number of patients first seek care. The technologies targeted for each level are intended to match the human resources available and the degree of complexity of the diagnostic question. Some of the diagnostic tools expected to be introduced into control programs will be incremental improvements on existing technologies while others will be radically new.

ASM, through its International Laboratory Capacity Building program, is ensuring the quality-assured implementation of new and existing diagnostic tools in resource-limited countries through onsite training and technical assistance. For this purpose, ASM is strengthening clinical microbiology laboratories by mobilizing its members to build human resource capacity for diagnosis of tuberculosis and other infectious diseases.

The memorandum of understanding is expected to serve as the beginning of a close collaboration between the ASM and FIND towards maximizing their complementary strengths and contributions to global health efforts.

Combination anti-retroviral therapy increases life expectancy by greater than 13 years

Fri, 25 Jul 2008 23:29:24 PST

( from http://www.rxpgnews.com ) The life expectancy for patients with human immunodeficiency virus (HIV) has increased by more than 13 years since the late 1990s thanks to advancements in antiretroviral therapy, according to researchers at the University of Alabama at Birmingham (UAB) and Simon Fraser University in Vancouver, British Columbia.

Improved survival has led to a nearly 40 percent drop in AIDS deaths among 43,355 HIV-positive study participants in Europe and North America, bolstering the call for improved anti-HIV efforts worldwide, the study authors said.

The study is published in the British medical journal The Lancet. It was compiled by The Antiretroviral Therapy Cohort Collaboration, which includes UAB, Simon Fraser University and more than a dozen other research sites around the world.

The authors looked at changes in life expectancy and mortality among the 43,355 HIV patients taking a cocktail of drugs called combination antiretroviral therapy (cART). Data was compiled from a total of 14 studies in Europe and North America.

"Since their introduction in 1996 cART regimens have become more effective, better tolerated and easier to follow," said Michael Mugavero, M.D., an assistant professor in UAB's Division of Infectious Diseases and a co-author on the study.

"We are now seeing the benefits of years of research, hard work and efforts to make these medications widely available. This has led to dramatic improvements in life expectancy, but patients who start cART with more advanced HIV infection do not have the same level of benefit," Mugavero said.

The new Lancet study found cART yielded a 13.8-year life-expectancy increase - from 36.1 years in study participants who began therapy during the 1996-1999 period to 49.9 years in participants who began therapy during the 2003-2005 period.

Despite the good results, the study found life expectancy for HIV patients is far lower on average than the general population, which includes all those with other chronic illnesses. For example, an HIV-positive patient starting cART at age 20 will live to 63, about 20 years shorter than the average life span of non-infected adults.

With nearly half of all patients diagnosed with advanced HIV infection, the life expectancy benefits of cART are not fully realized, said Mugavero and lead study author Robert Hogg, Ph.D., of Simon Fraser University. Improved AIDS testing and increased access to care is needed.

HIV-I knocks out immune system faster than thought

Sat, 19 Jul 2008 13:37:12 PST

( from http://www.rxpgnews.com ) Washington, July 19 - The HIV-I virus virtually knocks out the immune system much faster than previously thought.

The window of opportunity for successful intervention may be only a matter of days - not weeks - after transmission, according to scientists of Duke University Medical Centre.

The finding may compound the problem of the challenge of designing an effective HIV/AIDS vaccine. But it has also yielded a blueprint for what a successful vaccine should look like, and moreover, when such a vaccine would need to work.

Until now, scientists believed that the window of opportunity for intervention lasted three to four weeks between transmission and the development of an established pool of infected CD4 T cells. HIV-1 cripples the immune system by invading and killing CD4 T cells, key infection-fighters in the body.

'But this new study shows that HIV-I does a lot of damage to the immune system very early ... and now we feel that the opportunity to intervene most effectively may range from about five to seven days after infection,' said Barton Haynes, co-author of the study and director, Duke Centre for HIV/AIDS Vaccine Immunology -.

Haynes said the findings suggest that an optimal vaccine strategy would have to pack a double punch: First, establishing as much immunity as possible before infection, much as classic vaccines do, and then following a few days later with a mechanism to provoke a strong, secondary, broad-based antibody response.

'Vaccine candidates to date have pretty much followed a single strategy. Now we know that we need to activate multiple arms of the immune system and we have a better idea of when to do it.'

The conclusion is based on a study of 30 people who were newly-infected with HIV-I. Plasma from these individuals was sampled every three days for several months - before, during, and after the 'ramp-up' phase of infection, when HIV-I is multiplying rapidly and heading toward its peak viral load.

In measuring the levels of four products of CD4 T cell death during this period in these samples, they were able to track and establish a timetable of the virus's destructive path.

These findings will appear in the August issue of the Journal of Virology.

With $2M NIH grant, FSU becomes 1 of world's top imaging centers

Wed, 16 Jul 2008 03:59:37 PST

( from http://www.rxpgnews.com ) TALLAHASSEE, Fla. -- At Florida State University, the collective strength of biomedical research and the scientists who lead it has earned a $2 million High-End Instrumentation (HEI) grant from the National Institutes of Health (NIH). The one-year award will help FSU buy a state-of-the-art robotic electron microscope to advance cutting-edge studies of HIV/AIDS, heart disease, hypertension and cancer.

FSU will have $4.8 million in total funding after it matches the $2 million NIH award with $2.8 million from monies the university has set aside specifically to support research.

Installing this groundbreaking technology will place us among the very top imaging centers in the world, said FSU College of Arts and Sciences Dean Joseph Travis. He declared the competition unbelievably tough for HEI grants, which come from the National Center for Research Resources (NCRR), a part of NIH that provides laboratory scientists and clinical researchers with the tools and training they need to understand, detect, treat and prevent a wide range of diseases.

For its $4.8 million investment, FSU will get a fully automated cryo-electron microscope that provides rapid, 3-D imaging of frozen specimens around-the-clock via remote operation, then transmits them over the Internet. In addition to significantly speeding the collection of crucial data, researchers in biology and chemistry at FSU and colleagues at other institutions will get unprecedented views of -- and 24/7 access to -- the intricate interactions of individual proteins and molecular machines within the living cells of complex biological structures.

Currently, the world's only working installation of this microscope is in Germany, Travis said. In the U.S., FSU will have one of only four. The others will be installed at NIH itself; the University of California-Berkeley; and the National Center for Microscopy and Imaging Research at the University of California-San Diego -- all acknowledged as the best in the nation for structural biology and structural biological imaging. FSU soon will have capabilities unmatched by all but a few institutions in the nation.

Travis noted that it's extremely rare to see an HEI grant, especially such a large one, awarded to a single group of investigators; typically awards of that type go to national centers or nationwide facilities serving multiple groups. It's quite a testament to the scientific ingenuity of the group that will comprise the instrument's primary users, the importance of the work they do, and the commitment FSU has made to their research areas, he said.

Innovative biomedical research requires frequent access to the newest and most advanced technology, said Barbara Alving, M.D., director of NCRR. Such tools play key roles in the study of disease and the fundamental mechanisms of biological function, ultimately leading to new advances and treatments for diseases.

Expected to stand 16 feet high and weigh 1.7 tons, the new microscope will serve as a crucial tool to the cadre of FSU scientists who will share it once required renovations to the building in which it will be housed are completed in 2009.

This instrument will be cutting-edge in several ways, said biological science Professor Kenneth Taylor, the principal investigator on FSU's award-winning grant application.

Not only is it robotic, collecting data continually without operation attention, in fact it can only be operated remotely, Taylor said. There's no conventional 'binocular' for the user to view the image. What's more, the microscope can be operated and the images viewed by anyone in the U.S. with high-speed Internet capability and the required, specially designed workstation.

Five major FSU research projects helped secure the NIH-NCRR grant for 2008.

Among them is a cell adhesion study led by Taylor, a member of the unique interdisciplinary FSU Institute of Molecular Biophysics (

Increased diabetes risk in HIV -positive children; increased cholesterol with some treatments

Tue, 15 Jul 2008 11:44:49 PST

( from http://www.rxpgnews.com ) UC Davis researchers have found, that despite results to the contrary in adults, average cholesterol profiles in young children with HIV do not worsen when they are put on highly active antiretroviral therapy (HAART)--but only when certain combinations of drugs are used. The researchers also found that children beginning or switching to HAART also showed an increase in insulin resistance, potentially raising their risk of developing diabetes later in life.

"These children are facing a lifetime of potential complications, not just from their HIV infection, but from the drugs used to treat it," said Caroline Chantry, associate professor of pediatrics. The study is the largest to date looking at metabolic disruption caused by HIV and associated treatment in children before puberty. "We need to know now if these children will be at greater risk of developing heart disease or diabetes so that we can improve treatment and focus on prevention," Chantry said.

The current study was published online by Pediatrics on June 2.

The good news for patients, based on the current study, is that increasing CD4 T-cell counts--a measure of immune function used to gauge success of HAART--results in improvements in cholesterol levels. Their risk of diabetes, however, remains a concern because the children involved in the study showed increases in their bodies' resistance to the action of insulin, the hormone responsible for stabilizing blood glucose levels.

"The values were not so high as to diagnose them with diabetes, but insulin resistance is a risk factor for developing the disease," Chantry said. The issue will require further study, she added.

Chantry and her colleagues also discovered that improved lipid profiles paralleled improved sensitivity to growth hormone. This provides a clue to a possible cause of abnormal cholesterol in the infected children that could eventually lead to better treatment or prevention strategies. Children with HIV often suffer from stunted growth as a result of growth hormone resistance.

There is other good news with respect to the study's cholesterol findings, Chantry said. Physicians can further reduce their pediatric patients' risk of developing high cholesterol by simply changing the combination of drugs they are given as part of HAART. Children in the study had worse cholesterol profiles (lower levels of HDL, the so-called "good" cholesterol and a higher total to HDL cholesterol ratio) when a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor were used in combination, but not when either was used alone.

Previous studies had shown that adults and teenagers on HAART commonly showed increases in cardiovascular risk because of increased LDL levels and in insulin resistance. Chantry and her colleagues decided to take a look at these metabolic disturbances in younger patients.

The 97 children included in this study were part of the Pediatric AIDS Clinical Trials Group Protocol 1010, a multi-state 48-week observational study. They ranged in age from less than one-month to less than 13 years and had predominantly mild-to-moderate disease. To be included, the children had to either be starting HAART for the first time or changing treatment because other therapies had failed.

Blood samples were taken during the study. Fasting cholesterol, glucose, insulin and CD4 T-cells were among the blood levels measured. To analyze the data, each child was matched for age, gender and race/ethnicity with data from children in the National Health and Nutrition Examination Survey.

Researchers found that initiation or change in HAART in these children was associated with significant increases in T-cell counts, both bad (LDL) and good cholesterol (HDL) measures, sensitivity to growth hormone, and insulin resistance.

"We were very surprised to find out that overall cardiovascular risk does not increase for these children starting or switching HAART," Chantry said. The results showed that both HDL (good) and LDL (bad) cholesterol, increased, but the good more so than the bad. "There were some good changes and some not-so-good changes, but the net effect was no increased risk," she added, "and some children actually improved."

Doctors use a variety of combinations in HAART that can include one or the other or both of the classes of drugs known as protease inhibitors and non-nucleoside reverse transcriptase inhibitors. "The combinations that have both classes were worse for the patients in terms of lipid profiles," Chantry said. "Either one of these classes along with other types antiretrovirals is better than both together."

Keeping children with HIV healthy for as long as possible means looking at the way they are affected by the drugs used to treat them, Chantry said. "Children are not little adults. We are never sure until we look whether or not what is medically going on in adults is also going on in children."

New HIV browser gives researchers access to valuable data from vaccine trials

Thu, 29 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) SANTA CRUZ, CA--A new HIV data browser developed by the University of California, Santa Cruz, and the nonprofit organization Global Solutions for Infectious Diseases (GSID) will give researchers access to a wealth of data collected during clinical trials of an AIDS vaccine. Although the vaccine did not succeed in preventing infections, the clinical trial generated a huge amount of valuable data for researchers studying how the virus evolves and causes new infections.

Modeled on the UCSC Genome Browser, the GSID HIV Data Browser is the brainchild of Phillip Berman, professor and chair of biomolecular engineering in UCSC's Baskin School of Engineering. Berman helped oversee the clinical trials, which ended in 2003, when he was senior vice president for research and development at VaxGen, the company that developed the vaccine and conducted Phase III clinical trials in North America, Europe, and Thailand.

After the trials concluded, I spent a couple of years trying to think what was the most important thing I could do for HIV research, Berman said. I concluded it was using new technology to preserve the data from these clinical trials and present it in a form useful to the scientific community.

In 2004, Berman cofounded GSID, based in South San Francisco and dedicated to combining knowledge and expertise from the biotechnology industry and the public health sector to address infectious disease problems in the developing world. He joined the UCSC faculty in 2006.

Despite the fact that the vaccine trial didn't work, a huge amount of useful information was obtained, Berman said. The North American trial included about 60 different clinical sites in North America and one site in the Netherlands. Of particular value to researchers are the genetic sequences of the viruses that infected participants during the trial.

The trial represented the only up-to-date broad survey of virus sequences from new infections that had ever been carried out, Berman said. Every time there was a new infection in the vaccine or placebo group, the virus was sequenced. The sequence information provides the best picture we have about what the immune system sees when there is a new infection.

This is important, Berman said, because other major repositories of HIV sequence data are not annotated for the time after infection, the clinical status of the patient, or the histories of the specimens sequenced. That limits their usefulness for studying such a rapidly evolving virus.

HIV is highly mutable and evolves in response to attacks by the immune system. As a result, HIV isolated from a patient years after the initial infection is genetically different from the virus that caused the infection in the first place. A vaccine should target the most infectious form of the virus, Berman said. Yet all the vaccines tested so far have been based on viruses isolated from patients with longstanding infections.

A current hypothesis in HIV vaccine research is that the antigenic structures of HIV viruses that mediate new infections differ from those recovered from people long after infection, Berman explained. The specimens in this set represent the largest group from new infections that has ever been collected.

Besides viral genome-sequence data, the database links to a repository of preserved specimens (blood samples and cells) that researchers can access from GSID and the National Insitutes of Health (NIH) for further study.

This is the first time that an HIV sequence database has been linked to a specimen repository and a database of clinical information, Berman said. These clinical specimens are longitudinal, collected from the same person during a two-year follow-up period. This will allow investigators to study the evolution of the virus and the evolution of the immune response and clinical outcomes.

At UCSC, Berman teamed up with the Genome Browser group to develop a browser for the sensitive clinical data collected during the vaccine trial. Jim Kent, associate research scientist for the UCSC Genome Browser and principal investigator on the project, said it was the first time his group had worked with data from participants in a clinical trial.

This data must be handled differently and great care taken with confidentiality, Kent said. We learned from this project how to build the infrastructure to cope with that. This will be useful for other medical projects, such as cancer genomics, in the future.

Fan Hsu, director of proteomics for the UCSC Genome Browser, said the emphasis on security was very different from past projects. Before, everything we have worked on is totally open, totally public. With the GSID project, only authorized users can access the data, so we needed to set up special controls, Hsu said.

How to display the very large number of HIV sequences on the browser was another challenge. Our original genome browser has only one reference genome. For this HIV database, we have about 350 infected people and more than 1,000 sequences, he said.

Hsu and software developer Galt Barber adapted the genome browser software to accommodate the large number of HIV sequences and the data security along with interactive selection criteria for viewing the data. As the project evolved, Hsu also coordinated the transfer of the software to GSID. The UCSC team, which also included Erich Weiler, Robert Kuhn, and Ann Zweig, worked nights and weekends to bring the new browser online.

The resulting GSID HIV Data Browser is a customized version of the UCSC Genome Browser. It provides researchers with searchable demographic and clinical data from volunteers who became HIV infected during the VaxGen clinical trial. The browser allows users to align viral sequences with one another and with reference or consensus sequences.

This is something where the university can make a difference, because the private sector is not so interested in vaccines; they're not so profitable, Kent said. There is very little economic incentive to develop an AIDS vaccine, but there is a tremendous humanitarian incentive.

Kent hopes that just as the UCSC Genome Browser has continued to build the collaborative nature of the genomics research community, this HIV data browser will help motivate the AIDS research community to work together and pool their data.

Vaccine development efforts have been repeatedly frustrated. An HIV vaccine candidate developed by the pharmaceutical company Merck recently failed in clinical trials cosponsored by NIH. The recent failure of the Merck HIV vaccine has thrown the field into turmoil, Berman said. All the best ideas for an HIV vaccine in the past 20 years have failed. The information in this database is now more critical than anyone could have imagined. It tells us what's being transmitted.

The next phase of the HIV browser project involves releasing the sequence data from infected participants in the Phase III clinical trial that VaxGen conducted in Thailand.

In the future, the database will be expanded to allow associations between virus sequences, clinical data, immune response data, and host genetics, Berman said. We hope to eventually include data from other HIV vaccine trials sponsored by the NIH, private companies, and other HIV vaccine research organizations.

The formation of a HIV particle- imaged

Mon, 26 May 2008 04:39:07 PST

( from http://www.rxpgnews.com ) A mapmaker and a mathematician may seem like an unlikely duo, but together they worked out a way to measure longitude – and kept millions of sailors from getting lost at sea. Now, another unlikely duo, a virologist and a biophysicist at Rockefeller University, is making history of their own. By using a specialized microscope that only illuminates the cell’s surface, they have become the first to see, in real time and in plain view, hundreds of thousands of molecules coming together in a living cell to form a single particle of the virus that has, in less than 25 years, claimed more than 25 million lives: HIV.

This work, published in the May 25 advanced online issue of Nature, may not only prove useful in developing treatments for the millions around the globe still living with the lethal virus but the technique created to image its assembly may also change the way scientists think about and approach their own research.

“The use of this technique is almost unlimited,” says Nolwenn Jouvenet, a postdoc who spearheaded this project under the direction of HIV expert Paul Bieniasz and cellular biophysicist Sandy Simon, who has been developing the imaging technique since 1992. “Now that we can actually see a virus being born, it gives us the opportunity to answer previously unanswered questions, not only in virology but in biology in general.”

Unlike a classical microscope, which shines light through a whole cell, the technique called total internal reflection microscopy only illuminates the cell’s surface where HIV assembles. “The result is that you can see, in exquisite detail, only events at the cell surface. You never even illuminate anything inside of the cell so you can focus on what you are interested in seeing the moment it is happening,” says Simon, professor and head of the Laboratory of Cellular Biophysics.

When a beam of light passes through a piece of glass to a cell’s surface, the energy from the light propagates upward, illuminating the entire cell. But when that beam is brought to a steeper angle, the light’s energy reflects off the cell’s surface, illuminating only the events going on at its most outer membrane. By zeroing in at the cell’s surface, the team became the first to document the time it takes for each HIV particle, or virion, to assemble: five to six minutes. “At first, we had no idea whether it would take milliseconds or hours,” says Jouvenet. “We just didn’t know.”

“This is the first time anyone has seen a virus particle being born,” says Bieniasz, who is an associate professor and head of the Laboratory of Retrovirology at Rockefeller and a scientist at the Aaron Diamond AIDS Research Center. “Not just HIV,” he clarifies, “any virus.”

To prove that what they were watching was virus particles assembling at the surface (rather than an already assembled virion coming into their field of view from inside the cell), the group tagged a major viral protein, called the Gag protein, with molecules that fluoresce, but whose color would change as they packed closer together. Although many different components gather to form a single virion, the Gag protein is the only one necessary for assembly. It attaches to the inner face of the cell’s outer membrane and when enough Gag molecules flood an area, they coalesce in a way that spontaneously forms a sphere.

Simon, Bieniasz and Jouvenet found that the Gag molecules are recruited from the inside of the cell and travel to the cell’s surface. When enough Gag molecules get close and start bumping into each other, the cell’s outer membrane starts to bulge outward into a budding virion and then pinches off to form an individual, infectious particle. At this point, the researchers showed that the virion is a lone entity, no longer exchanging resources with the cell. By using tricks from optics and physiology, they were able to watch the steps of viral assembly, budding, and even scission off the cell surface. With such a view they can start to describe the entire lifeline in the birth of the virus.

“I think that you can begin to understand events on a different level if you actually watch them happen instead of inferring that they might occur using other techniques,” says Bieniasz. “This technique and this collaboration made that possible.”

Scientists identify key roadblock to gene expression

Thu, 08 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A team of scientists has provided, for the first time, a detailed map of how the building blocks of chromosomes, the cellular structures that contain genes, are organized in the fruit fly Drosophila melanogaster. The work identifies a critical stop sign for transcription, the first step in gene expression, and has implications for understanding how the AIDS virus regulates its genes. The findings will be published in the 15 May 2008 issue of the journal Nature.

The scientists found that nucleosomes--chromosomal building blocks made up of proteins around which DNA is coiled--occur at precise locations along genes that are actively undergoing transcription. They also showed that RNA polymerase--the enzyme that reads genes as the first step in making proteins--is stopped at the first nucleosome, where it remains idle until it is directed to continue moving forward. This discovery is important because nucleosomes are barriers to transcription and we now are seeing the impact of nucleosome organization on RNA polymerase, said lead investigator B. Franklin Pugh, professor and Willaman Chair in Molecular Biology at Penn State University.

Using state-of-the-art ChIP-sequencing, a genome-mapping tool provided by collaborator Stephen S. Schuster, Penn State professor of biochemistry and molecular biology, and computational predictions developed by collaborators Ilya Ioshikhes, an assistant professor at Ohio State University, and Istvan Albert, a research assistant professor of bioinformatics at Penn State, the scientists precisely mapped the locations of hundreds of thousands of nucleosomes. The scientists then compared these maps to the team's earlier maps of the baker's yeast Saccharomyces cerevisiae, revealing that evolution has organized nucleosomes differently in simple life forms compared to more complex organisms like the fruit fly.

In yeast, a nucleosome sits on top of the transcription start site, so RNA polymerase must contend with that nucleosome as soon as it begins to transcribe the gene. In contrast, nucleosomes are positioned further downstream in fruit flies, so transcription starts but then soon pauses at the first nucleosome the RNA polymerase encounters. This pause is maintained until chemical signals from the cell cue the removal of the nucleosome and encourage the RNA polymerase to continue along its path, said key collaborator David S. Gilmour, professor of molecular and cellular biology at Penn State and an expert on the pausing of RNA polymerase.

A year ago, we could name about 10 genes that work this way. Now, we know of 1,000 in flies alone and we suspect there could be many more in humans, said Gilmour. Even HIV genes have a paused RNA polymerase. Release of this pause may be key to activating HIV replication of otherwise latent viruses. Taking advantage of this new understanding might enable the development of more effective anti-viral drugs, he said.

The bottom line is that we need to know how the expression of genes is regulated in order to understand the underpinnings of most human diseases, and these findings take us one step closer, said Pugh.

Molecular espionage shows a single HIV enzyme's many tasks

Wed, 07 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) CAMBRIDGE, Mass. -- Using ingenious molecular espionage, scientists have found how a single key enzyme, seemingly the Swiss army knife in HIV's toolbox, differentiates and dynamically binds both DNA and RNA as part of the virus' fierce attack on host cells. The work is described this week in the journal Nature.

The enzyme, reverse transcriptase (RT), is already the target of two of the three major classes of existing anti-HIV drugs. The new work, using single-molecule fluorescent imaging to trace RT's activity in real time, not only reveals novel insights into how this critical viral enzyme functions, but also clarifies how some of the anti-HIV pharmaceuticals work.

The research team, at Harvard University and the National Cancer Institute, was led by Xiaowei Zhuang at Harvard and Stuart Le Grice at NCI. Elio A. Abbondanzieri at Harvard and Gregory Bokinsky, formerly at Harvard and now at the Lawrence Berkeley National Laboratory, are lead authors.

Our experiments allowed us, for the first time, a peek at how individual RT molecules interact with the HIV genome, says Zhuang, professor of chemistry and chemical biology and of physics in Harvard's Faculty of Arts and Sciences, as well as an investigator with the Howard Hughes Medical Institute. We found that RT binds RNA and DNA primers with opposite orientations and that RT's function is dictated by this binding orientation.

HIV begins its assault by injecting its single-stranded RNA into a host cell. Three subsequent steps are all mediated by RT: The viral RNA is converted into single-stranded DNA, the single-stranded DNA is replicated into double-stranded DNA, and the original viral RNA is degraded. Another enzyme mediates the final step of the genome conversion, where the viral double-stranded DNA is inserted into the host's DNA, allowing it to take advantage of the host's genetic machinery to replicate and propagate itself.

Using their molecular probe to spy on this process, Abbondanzieri and colleagues traced RT's multitasking skill to its dynamic active sites, which allow it to bind and process RNA as well as single- or double-stranded DNA.

Remarkably, RT can spontaneously flip between these two opposite orientations on DNA and RNA to facilitate two distinct catalytic activities, says Abbondanzieri, a postdoctoral researcher in Harvard's Department of Chemistry and Chemical Biology. These flipping motions, which have never before been seen in a protein-nucleic acid complex, can be likened to a nanoscale version of a gymnastics routine on a pommel horse.

The 180-degree flipping of RT is regulated by nonnucleoside RT inhibitors (NNRTIs), a major class of anti-HIV drugs. Abbondanzieri and coworkers observed NNRTIs inhibiting HIV activity by accelerating RT's flipping between its two active sites, hindering the enzyme's ability to convert single-stranded DNA to double-stranded DNA.

Stanford researchers synthesize compound to flush HIV out of hiding

Thu, 01 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Any hunter will tell you that when your quarry goes into hiding, you have to flush it out to get a good shot at it. Such is the case with HIV, the virus that causes AIDS.

Though antiretroviral cocktails can target an active infection, they cannot get at the virus when it retreats inside the host's T cells, where it may lie dormant for decades, waiting for an opportunity to burst forth in a fresh round of infection. What HIV hunters need is a good bird dog.

Now, Stanford chemist Paul Wender and his coworkers have found a way to synthesize better bird dogs, agents that can be tailored to flush HIV out into the open where the immune system and antiretroviral therapies can destroy it. Wender is senior author of a paper about the research in the May 2 issue of Science.

We're not sure how far this will go, but certainly, from a theoretical point of view, it has promise of taking therapy to the next level-that is, addressing issues related to eradication of the disease, of the virus, at least, said Wender, the Francis W. Bergstrom Professor.

Wender and his co-workers Jung-Min Kee and Jeff Warrington have developed a way to synthesize prostratin and DPP, two compounds that occur naturally in plants, in the laboratory. Prostratin, found in the Mamala plant (Homalanthus nutans) that grows in the Samoan rainforest, has shown promise in previous studies as an activator of dormant HIV. DPP, a molecular relative of prostratin found in resin spurge (Euphorbia resinifera), which grows in arid regions, also has shown potential.

Research has been hampered, though, because the compounds are difficult to obtain, particularly in the quantities needed for practical lab work on their mode of action and therapeutic potential. The yield from both plants is low and highly variable; the availability of the plants is limited; and isolating the compound is difficult. Heavy harvesting of the wild plants, especially in Samoa, also could cause ecological damage.

But synthetic prostratin and DPP, which now can be readily made in the lab, changes that equation.

We have now minimized, if not eliminated, the issue of availability of prostratin and DPP, Wender said. But equally, if not more importantly, we have opened access to other compounds that might be similar in structure but superior in function.

Previous work done in mice by researchers at the University of California-Los Angeles indicates that prostratin, used in combination with interleukin-7, an immune system stimulator made in bone marrow, managed to flush out and eliminate approximately 80 percent of the dormant virus. But with HIV, 80-percent efficiency is not enough. Anything less than 100 percent means the virus is still lurking in the T-cells and will spring back to action as soon as an opportunity presents itself.

Nature has produced these compounds for various reasons in the plants from which they're derived, but certainly not to treat human maladies, Wender said. They're not optimized for human therapy.

But with synthetic prostratin and DPP available, researchers can take the basic compounds and tinker with the structure and related function. We could find out how to improve them by reverse engineering: figuring out what is important and what isn't important, Wender said. We could begin to design and synthesize molecules that would never be found in nature but might actually be therapeutically more beneficial than what has been found thus far.

In the Science paper, Wender and his team detail how both compounds can be synthesized, but also show the initial phase of designing and making new derivative compounds.

Although prostratin has long been used by traditional Samoan healers without their patients experiencing acute side effects, it is possible that undesirable effects could show up in an immune-impaired patient taking prostratin or DPP. But Wender noted that engineering the compounds in a lab would permit scientists to circumvent these problems. Usually these kinds of side effects are a result of a drug hitting multiple targets. So it hits one target, which is beneficial, but then it hits some other target, too, he said. But by modifying the structures, you could select for the beneficial activity over the non-beneficial activity.

It's a little bit like draw poker, Wender said. The important point is that we're not forced to use the hand we get. We'll get a hand and we'll return a few cards if we don't like it, because we can keep on tuning this until we get it right, so that a royal flush, hopefully, can be realized.

Wender's team developed their method of synthesizing prostratin and DPP by using a renewable resource, croton oil, made from the seeds of a small tree (Croton tiglium) cultivated in Asia. They derived phorbol from the croton oil and then converted it into the structure of prostratin.

The conversion process required some engineering finesse; they had to overcome a hurdle when, by removing an oxygen atom, they triggered a series of anticipated but seemingly undesired changes.

To the credit of my coworkers, Jung-Min Kee and Jeff Warrington, they employed a strategy that sometimes is missed, Wender said. Rather than fighting the flow, they went with it. They found a way to redirect the chemical complications into a solution to the problem that proved even better than the route they had initially sought to follow.

Eventually they produced a shorter, more economical way of connecting our starting material, phorbol, to our target, prostratin, Wender said. The process Kee and Warrington came up with requires only five steps, which is of tremendous importance in making it economically feasible. As Wender pointed out, steps cost money and human time.

Wender emphasized that the work of his team is the most recent chapter in efforts of a truly global community, starting with the Samoan healers, who willingly shared their knowledge with Paul Cox, an ethnobotanist who saw them prescribing a tea made from Mamala bark for patients with hepatitis-like symptoms. Cox, in turn, sent samples to the National Institutes of Health, in hopes that the bark might have antiviral properties useful in fighting some cancers. Researchers at NIH then analyzed the bark and isolated prostratin.

Prostratin belongs to a class of compounds called tiglianes, many of which promote tumor growth, so it had no initially perceived use in fighting cancer. But NIH researchers found that prostratin was not a tumor promoter and checked to see if perhaps it could help combat HIV, which is when its remarkable ability to flush out the dormant virus was discovered. Significantly, prostratin has also been found to block uptake of the purged virus, offering yet another potentially therapeutic benefit.

The whole effort is a testimonial to a global community working to deal with what I think is a global, and top priority, problem, Wender said.

UT-ORNL and UCSD researchers find promise in HIV 'switch'

Sun, 16 Mar 2008 03:59:37 PST

( from http://www.rxpgnews.com ) KNOXVILLE -- If the battle against HIV, the virus that causes AIDS, is a chess match, then new research published today gives new insight into one of the virus' most important moves.

The findings, by University of Tennessee, Knoxville, and Oak Ridge National Laboratory researchers Michael Simpson and Roy Dar, with colleague Leor Weinberger who led the research at the University of California, San Diego, reveal new information about how a critical genetic switch in the virus operates. They are published as a letter in the upcoming issue of Nature Genetics.

When HIV infects an immune cell, it can enter one of two states: activation, where the virus replicates and then destroys the host cell; and latency, where the viral genetic material continues to exist in the cell, but there is no production of additional virus.

While latency is a ticking time bomb, said Simpson, a possible therapeutic goal could be to stably maintain latency indefinitely.

Previous work by Weinberger found that the genetic circuit that controls whether HIV chooses to go active or latent is not a simple on-off switch, but instead is controlled by a type of genetic pulse -- when the pulse lasts a certain amount of time, the switch will activate replication of the virus.

Now the three researchers have demonstrated that it is possible to manipulate the lengths of the pulses in a way that would favor the selection of latency.

This is vital, said Simpson, because the switch is a definitive factor in whether the virus will become active. If the pulse does not last long enough, he said, the virus cannot become active.

This is an early step, but an encouraging one, said Simpson. HIV has evolved a very effective infection strategy, so the name of the game is understanding how that strategy operates in order to find a way to defeat it.

A challenge of the work, according to Simpson, is that the process involved in how the switch operates cannot be directly observed. Instead, the researchers had to rely on an analysis of the noise created within the cell by the process to determine how it worked.

Simpson and Dar conducted their work in the Center for Nanophase Materials Science at ORNL, a recently opened facility that Simpson says has made this type of analysis possible.

Moving forward, the next step in the research is to determine whether it is viable to attempt to control the switch as part of therapeutic treatment for HIV. The researchers also hope to apply the techniques they used to understanding the operation of other types of human cells.

Scientists say tropics are next emerging disease hotspot

Thu, 13 Mar 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists from four well-known institutions say the next major disease like HIV/AIDS or SARS could occur in any of a number of developing countries concentrated along the equator. They encourage increased surveillance to prevent the spread of a potential outbreak.

Using global databases and sophisticated computer models to analyze patterns of emerging diseases, the researchers -- from the Consortium for Conservation Medicine (CCM) at Wildlife Trust, N.Y., the Institute of Zoology, London, U.K., Columbia University, N.Y., and the University of Georgia, Athens, Ga. -- are able for the first time to plot, map and predict where the next pandemic might occur.

Funded through a Human and Social Dynamics Exploratory Research award from the National Science Foundation (NSF), Arlington, Va., the research represents a major breakthrough in understanding where and why pandemic diseases emerge and provides a key tool for preventing them in the future.

This is an important area of research, said Rita Teutonico, advisor for integrative activities in NSF's Directorate for Social, Behavioral and Economic Sciences. After years of debate, the scientific community is now able to offer a convincing, predictive tool to help policy professionals and resource managers better allocate global resources in the fight against emerging diseases.

By analyzing global patterns in human population density, population changes, latitude, rainfall and wildlife biodiversity in correlation with patterns of emerging diseases, the researchers were able to show for the first time definitive proof that the number of emerging diseases is increasing.

They cite zoonoses -- diseases that originate in animals -- as the primary problem and conclude these are the most current and important threat to humans. The research shows that the key threat to public health is where human population growth and wildlife diversity clash, said Peter Daszak, executive director of the Consortium for Conservation Medicine at Wildlife Trust.

The scientists analyzed 335 incidents of previous disease emergence and were able to identify the regions where future diseases were most likely to occur. They plotted the results on a global, Emerging Disease Hotspots map.

Our hotspots map shows that the next new important zoonotic disease is likely to originate in the Tropics, a region rich in wildlife species and under increasing pressure from people, Daszak said.

This is the first time researchers are able to provide a scientific prediction of where the next major disease like HIV or SARS could emerge. During the last three decades, researchers have spent billions of research dollars to deal with the seemingly random emergence of dozens of pandemics. None of their efforts to understand patterns of emergence were successful.

This new research, published in the February 21 edition of the leading scientific journal Nature, successfully examined over 50 years of disease emergence patterns using a specially designed computer database to pinpoint regions of the world that need more monitoring.

This is a seminal moment in how we study emerging diseases, said Professor John Gittleman, dean in the University of Georgia's Odum School of Ecology, who developed the team's approach to analyzing global databases.Our study has shown that bringing ecological sciences and public health together can advance the field in a dramatic way.

But in light of this new information, the researchers note that additional resources need to be properly directed to safeguard public health.

Most of our resources are focused on the richer countries in the North that can afford surveillance, said Daszak. This is basically a misallocation of global health funding, and our priority should be to set up 'smart surveillance' measures in the hotspots, most of which are in developing countries.

If we continue to ignore this important preventative measure, then human populations will continue to be at risk from pandemic diseases, he said.

Novel mathematical model predicts new wave of drug-resistant HIV infections in San Francisco

Sun, 17 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) A mathematical model shows that a new wave of drug-resistant HIV is rising among among men in San Francisco who have sex with men and that this trend will continue over the next few years, according to a new study from the UCLA AIDS Institute.

At the same time, the evolution of drug-resistant HIV may have actually reduced the severity of the city's epidemic, saving many men from becoming infected.

The model and its results were unveiled today by UCLA biomathematics professor Sally Blower, director of the Biomedical Modeling Center at the David Geffen School of Medicine at UCLA, during a session on drug-resistant diseases at the annual American Association for the Advancement of Science conference in Boston.

Our amplification cascade model has been validated by our reconstructions and can now be used to design novel and effective health policies for controlling single-, dual- and triple-class resistant strains of HIV in both resource-rich and resource-constrained countries, said Blower, who is also a member of the UCLA AIDS Institute.

The model enabled the researchers to reconstruct the epidemic's past and predict its future by calculating the evolution of several classes of drug-resistant HIV strains in San Francisco.

The research relied on a novel multi-strain mathematical model called the Amplification Cascade Model to examine the rise between 1987 and 2007 of HIV strains resistant to the three major classes of drugs -- nucleosides (NRTIs), nonnucleosides (NNRTIs) and protease inhibitors (PIs). The model took into account three interacting processes -- transmitted, acquired and amplified resistance -- the last of which refers to amplification of drug-resistant strains in HIV-positive people due to the repeated use of multiple-treatment drug regimens.

The study tracked uninfected individuals; newly infected people in the primary stage of infection; chronically infected individuals who were not yet eligible for treatment; chronically infected people who remained untreated, though eligible for it; and patients under treatment.

Researchers found complex waves of rising and falling single-, dual- and triple-class drug-resistant HIV strains over 20 years, with more complex patterns continuing to evolve.

The model predicts that resistance to NRTIs will decline substantially and PI resistance will fall slightly through 2012, and that resistance to NNRTIs will rise over the next five years and then begin falling.

Although strains with dual- and triple-class resistance will be transmitted, they will be far less potent than wild-type HIV strains -- those strains that have not developed drug-resistant mutations and remain sensitive to all classes of drugs.

Most surprising of all, the evolution of drug-resistant HIV strains has substantially reduced the severity of the San Francisco AIDS epidemic because the strains that have emerged have become less infectious than the wild-type strains.

Enzyme structure reveals new drug targets for cancer and other diseases

Thu, 14 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) If the genome is the parts list of the human cell, certain proteins are the production managers, activating and deactivating genes as needed. Scientists funded by the National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health, now have a clearer understanding of how a key protein controls gene activity and how mutations in the protein may cause disease. The work could provide new avenues to design drugs aimed at cancer, diabetes, HIV, and heart disease.

The research appears in the Feb. 14, 2008, issue of the journal Nature. The lead authors include Philip Cole, M.D., Ph.D., of the Johns Hopkins University School of Medicine in Baltimore, Md., and Ronen Marmorstein, Ph.D., of the Wistar Institute in Philadelphia, Pa.

The investigators focused on a protein called p300/CBP that belongs to a family of enzymes known as histone acetyltransferases, or HATs. These enzymes activate genes by attaching chemicals called acetyl groups to histones, the spool-like proteins that hold DNA in a tightly wound form.

Mutations in p300/CBP are linked to a variety of cancers, including those of the colon, breast, pancreas, and prostate. Researchers believe that a substance that selectively inhibits p300/CBP might be the basis for an anticancer agent.

Nearly 10 years ago, Cole and his coworkers designed a p300/CBP inhibitor. But the inhibitor is not active in the human body, so it has been used exclusively as a research tool.

In the new study, the investigators combined X-ray crystallography with detailed enzymology to understand how p300/CBP works.

Their three-dimensional crystal structure provides an image of how a key part of p300/CBP binds to the inhibitor. Their studies of numerous mutant versions of the enzyme reveal which amino acids in p300/CBP are essential for its activity.

The work has a number of clinical implications. Understanding the structure and behavior of p300/CBP will help scientists design a p300/CBP inhibitor that might function in human cells as an anticancer drug.

Proper functioning of p300/CBP is critical for insulin regulation and the health of heart cells. As a result, compounds that can regulate p300/CBP activity might be useful in the treatment of diabetes and heart disease.

In addition, HAT activity is necessary for the multiplication of HIV, leading at least one scientific group to suggest that targeting HATs or similar enzymes might be an new way to thwart the virus.

Finally, the article also shows that some p300/CBP mutations previously linked to certain cancers lie right where p300/CBP contacts the inhibitor. Studying how these mutations alter the enzyme's function should shed light on why the mutations can lead to disease.

This work illustrates how enzymology and structural biology can combine to yield both fundamental and practical insights about an important biomedical problem. The studies provide a new framework for understanding p300/CBP in health and disease, said Jeremy M. Berg, NIGMS Director.

HIV persists in the gut despite long-term HIV therapy

Wed, 13 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Even with effective anti-HIV therapies, doctors still have not been able to eradicate the virus from infected individuals who are receiving such treatments, largely because of the persistence of HIV in hideouts known as viral reservoirs. One important reservoir is the gut, where HIV causes much of its damage due to the large number of HIV target cells that reside there. These cells, known as CD4+ T cells, are largely contained in lymph nodes and patches of lymphocytes that collectively are called gut-associated lymphoid tissue, or GALT.

Because of the importance of the gut to HIV disease, scientists hoped that long-term treatment with antiretroviral drugs could eradicate HIV from the GALT. A new NIAID study, published online by The Journal of Infectious Diseases, has found that this goal seems unlikely with current antiretroviral drugs.

Tae-Wook Chun, Ph.D., of the NIAID Laboratory of Immunoregulation (LIR), Anthony S. Fauci, M.D., LIR chief and NIAID director, and their colleagues intensively studied eight patients receiving effective antiretroviral therapy for up to 9.9 years. In each of these of these individuals, therapy had consistently kept their blood levels of HIV at undetectable levels. Sensitive tests, however, detected the persistence of HIV as well as lowered CD4+ T cell levels in the GALT that did not completely rebound in response to therapy. Levels of virus were higher in the GALT than in immune cells in the blood, where HIV also was consistently found. In addition, the scientists found evidence of cross infection between the GALT and the lymphocytes in the blood, suggesting that one reason the virus persists in the blood is because of ongoing cycles of replication in the GALT. The authors conclude that any possibility of further lowering or eliminating viral reservoirs likely will require more powerful drug regimens to stop the low levels of ongoing viral replication originating in the GALT. The development of such regimens is an important goal of NIAID-supported research.

A second study from the Fauci laboratory, conducted by Susan Moir, Ph.D., and her colleagues and also published online by The Journal of Infectious Diseases provides additional insights into the effects of antiretroviral therapy on the HIV disease process.

In most HIV-infected individuals, the virus replicates at high levels and CD4+ T-cell numbers decline. These two factors also strongly affect B cells, the cells of the immune system that make antibodies and help protect against infection. Dr. Moir and her colleagues demonstrated that prior to treatment with antiretroviral therapy, B-cell numbers in the blood of HIV-infected individuals who have been infected for several years are low, and the B cells also include several dysfunctional subsets. After one year of effective treatment with antiretroviral therapy, B-cell numbers returned to normal, and several of the dysfunctional subsets also normalized. However, those B-cells that provide long-term protection against infection--so-called memory B cells--did not return to normal levels. Dr. Moir notes that these findings strengthen the notion that while antiretroviral therapy improves many aspects of immune function in HIV-infected individuals, important deficiencies remain, especially in individuals who wait several years before initiating therapy. More studies are needed to determine whether early initiation of antiretroviral therapy helps restore the immune system more completely.

HIV drugs, Abacavir and Didanosine increase the risk of heart attack

Fri, 08 Feb 2008 04:24:37 PST

( from http://www.rxpgnews.com ) A study to assess the adverse effects of anti-retroviral drugs
shows that two widely-used HIV drugs are associated with
an increased risk of heart attack/the formation of blood clots in
the heart. With the use of Didanosine, the risk of developing a
heart attack increases by 49%, with Abacavir; the increased risk
is 90%. The effect is most pronounced in patients with a high
underlying cardiovascular risk. The research findings also show
that the adverse effect is reversible, if patients discontinue use
of these particular drugs.

The scientists who conducted the study recommend that patients
on Abacavir or Didanosine should evaluate their underlying
cardiovascular risk with their doctor and discuss whether any
changes to their drug regime are warranted. The scientists
strongly urge HIV patients not to stop taking Abacavir or
Didanosine, before they have consulted their doctor.

Since the study began in 1999, D:A:D (the Data Collection of Adverse
effects of Anti-HIV Drugs Study) has examined the side-effects of
anti-retroviral drugs, including a possible increase in the risk of heart
attack. Recent analysis has focused on a class of drugs, not previously
examined, known as the nucleoside analogues, which inhibit the HIV
virus by preventing it from multiplying. This class of drugs includes Stavudine, Zidovudine, Lamivudine, Abacavir and Didanosine. Only the last two drugs in the analysis were shown to have an adverse effect with respect to heart disease.

The side-effects associated with Didanosine and Abacavir are, naturally, most significant for HIV-infected patients who already have a high underlying cardiovascular risk. The drug effect increases an individual persons underlying risk by a factor
of 1.9 for a person on Abacavir, and 1.49 for a person on Didanosine. For a person with a low underlying risk, this increase in risk is still negligible, but for someone with a high
underlying risk, this could have serious consequences. The study shows, however, that the risk of heart attack is removed once patients stop taking the drugs. This seems to be the case, regardless of
how long these drugs have been used by patients.

The D:A:D study involves over 33,000 patients from Europe, Australia and Asia. The study evaluates the incidence of heart attack among HIV-infected patients undergoing anti-retroviral treatment, and thereby enables scientists to determine whether side-effects of the anti-retroviral drugs, including cardiovascular disease, are increased in the long-term.

Breastfeeding now safer for infants of HIV-infected mothers

Tue, 05 Feb 2008 20:29:37 PST

( from http://www.rxpgnews.com ) An antiretroviral drug already in widespread use in the developing world to prevent the transmission of HIV from infected mothers to their newborns during childbirth has also been found to substantially cut the risk of subsequent HIV transmission during breast-feeding.

In a study presented Feb. 4 at the 2008 Conference on Retroviruses and Opportunistic Infections in Boston, an international team of AIDS experts reports that nevirapine given once daily to breast-feeding infants from 8 to 42 days old decreased by almost half the rate of HIV transmission via breast-feeding at 6 weeks of age. The decrease occurred in comparison to a single dose of nevirapine given to infants at birth, the current standard of care. At 6 months of age, the risk of postnatal HIV infection or death in infants who received the six-week regimen was almost one-third less than the risk for infants given only a single dose. The study was led by three teams of investigators at The Johns Hopkins University in collaboration with investigators in Ethiopia, India and Uganda.

Breast-feeding remains a leading route of HIV transmission in the developing world. The United Nations World Health Organization estimates that approximately 150,000 infants are infected through breast-feeding each year. In the United States each year, fewer than 150 newborns are infected with HIV at birth, mostly to mothers who did not know they were HIV positive.

Eltrombopag effective for hepatitis C patients with low blood-platelet counts

Fri, 28 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 28, 2007) -- For patients with hepatitis C, having a low blood platelet count is a frequent complication associated with advanced disease. This problem is compounded by the fact that standard antiviral treatment for the disease can further reduce platelet numbers to dangerously low levels, effectively denying these patients the treatment they urgently need. Now, research published in the New England Journal of Medicine finds that a new drug, eltrombopag, appears to significantly boost platelet counts, opening the door to effective treatment.

In this study, eltrombopag increased platelet counts in a dose-dependent manner, allowing more patients to complete the first 12 weeks of antiviral therapy -- an important treatment goal, says Dr. Samuel Sigal, who led the study at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City -- one of 22 study sites.

Dr. Sigal is assistant professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College and assistant attending hepatologist in the Center for Liver Diseases and Transplantation at NewYork-Presbyterian/Weill Cornell.

The Phase 2 placebo-controlled study followed 74 patients with low platelet counts and cirrhosis of the liver due to hepatitis C virus (HCV) infection. Seventy-four percent of those randomized to take the lowest dose (30 milligrams daily) saw their platelet counts go up significantly, while 79 percent and 95 percent of the participants saw increases with the higher doses (50 or 75 milligrams daily, respectively). And, 12 weeks of antiviral therapy were completed by 36, 53 and 65 percent of patients at the three dose levels -- with increased numbers matched to the size of the dose. Underlining the trend, less than a quarter of patients receiving placebo completed their therapy.

The study identified side effects -- including headaches, dry mouth, abdominal pain and nausea. None were serious enough to discontinue the therapy.

It's estimated that 4 million people in the U.S. and 170 million worldwide carry the hepatitis C virus. HCV is transmitted primarily by blood and blood products. The majority of infected individuals have either received blood transfusions prior to 1990 (when screening of the blood supply for HCV was implemented) or have used intravenous drugs. More rarely, it can also be transmitted through sexual intercourse and perinatally (mother to baby).

The virus causes inflammation and scarring in the liver, and while it is curable in about half of those who have it, it can lead to significant liver damage, liver cancer and death in others. HCV infection is a common cause of cirrhosis and the most common reason for a liver transplant.

With other eltrombopag findings, NewYork-Presbyterian/Weill Cornell's Dr. James Bussel led research, also reported in the New England Journal of Medicine, finding the platelet growth factor successfully increased platelet counts and decreased bleeding in patients with Immune Thrombocytopenic Purpura (ITP), an autoimmune disease that dramatically reduces the number of platelets in their blood. (Dr. Bussel is an Advisory Board Member for GlaxoSmithKline; has received research grant support, lecture fees, and consulting fees from GlaxoSmithKline; and reports equity ownership in the company.)

The current study was sponsored by GlaxoSmithKline, which is developing eltrombopag. Eltrombopag (marketed as Promacta in the U.S. and Revolade in Europe) is an investigational oral, non-peptide platelet growth factor that induces the proliferation and differentiation of cells to produce platelets. While other drugs that restore normal platelet functions are infusions or injections, eltrombopag is a once-a-day pill.

2 genes are important key to regulating immune response

Fri, 28 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 28, 2007) -- A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).

The discovery fills in an important missing link in a biochemical pathway that's long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.

IL-10 production has to be kept in a delicate balance for health, explains study senior researcher Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell. Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology. Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and -- potentially -- how to better treat them, he says.

The findings are reported in this month's issue of Immunity (vol. 27).

Dr. Jianguo Liu, of Weill Cornell, and Dr. Elaine Y. Chung, formerly of Weill Cornell and now a post-doc at the University of Pennsylvania, were co-lead researchers on the study.

Every second, millions of the body's cells undergo naturally programmed cell death -- a process called apoptosis. In healthy individuals, these dying or dead cells are spotted and then quickly ingested and removed by immune system scavenger cells such as macrophages.

However, to prevent this type of clean-up from triggering a wider immune response, macrophages express the IL-10 cytokine in the presence of apoptotic cells.

IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explains.

That can be a good thing, of course, he says. But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy.

All of this means that anything that we can learn about IL-10 production -- and related T-cell suppression -- is a boon to medical research, Dr. Ma explains.

Prior studies had already shown that CD36 -- a protein receptor lying on the surface of the macrophage -- was important for the recognition of apoptotic cells by macrophages. In this work, the researchers observed that CD36 also helped to trigger IL-10 production whenever apoptotic cells were around.

The team then asked a deeper question: What signals lead to IL-10 production from CD36 present at the cell surface

To find out, the Weill Cornell group first exposed macrophages to apoptotic (dying) cells. They then used sensitive assays to look for key biochemical changes occurring downstream of CD36 activation.

We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells, Dr. Ma says. In subsequent biochemical experiments, the team identified the two genes responsible for the transcription (gene-directed production) of these proteins.

These genes -- pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) -- are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.

In that sense, their presence as immune system transcription factors came as a big surprise to us, Dr. Ma says. In fact, we still haven't figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there's a brand new biochemical pathway to be discovered.

The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.

Because IL-10 expression (and related T-cell suppression) are so important to the etiology of so many illnesses, discoveries like ours could point to molecular pathways that may become important new targets for drug discovery going forward, Dr. Ma explains. It's these types of breakthroughs in the lab that -- step by step -- will end up bringing real hope to patients down the line.

Dr. Lewis Drusin receives American College of Physicians James D. Bruce Memorial Award

Wed, 19 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 19, 2007) -- In recognition of his distinguished contributions in preventive medicine, epidemiologist Dr. Lewis Drusin of NewYork-Presbyterian Hospital/Weill Cornell Medical Center has been selected by the American College of Physicians to receive the prestigious James D. Bruce Memorial Award, one of 17 awards in internal medicine for 2008.

The convocation ceremony will take place on May 15, 2008, at the annual meeting of the American College of Physicians in Washington, D.C.

Past recipients include such notables as Nobel Prize winner Dr. Jonas Salk (polio vaccine), Dr. Donald Henderson (smallpox) and NewYork-Presbyterian/Weill Cornell's Dr. Walsh McDermott, who served as a mentor to Dr. Drusin.

Dr. Drusin is professor of clinical medicine and professor of clinical public health at Weill Cornell Medical College, and attending physician at NewYork-Presbyterian/Weill Cornell, where he was formerly director of the Division of Epidemiology.

We want to extend our congratulations to Dr. Drusin, whose career-long contributions to preventive medicine make him very deserving of this special honor, say Dr. Antonio M. Gotto, Jr., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, and Dr. Herbert Pardes, president and CEO of NewYork-Presbyterian Hospital.

Dr. Drusin has made outstanding contributions to the prevention and study of nosocomial infections and sexually transmitted diseases, publishing more than 50 papers and book chapters. At Weill Cornell, he directs a program placing Public Health and Community Medicine clerkship students in field locations, and has helped establish an endowment that offers international rotations to medical students. He served as president of the American Venereal Disease Association (now the American STD Association), and he has held prominent roles in many international scientific congresses and study groups relating to sexually transmitted diseases. Since 1995, he has served as the main representative of the International Union Against Sexually Transmitted Infections to the Economic and Social Council of the United Nations. He is a fellow of the American College of Physicians, a fellow of the Royal College of Physicians of London and one of only two American honorary life members of the British Association for Sexual Health and HIV.

He earned his undergraduate degree at Union College (Schenectady, N.Y.) and received his medical degree from Cornell University Medical College (now Weill Cornell Medical College). Dr. Drusin also holds an M.P.H. from the Columbia University School of Public Health.

I am deeply honored to be considered among such esteemed company, says Dr. Drusin. It is exiting when you make your career choices according to what's fun to do, and then you find out later that other people have appreciated what you've done.

HIV's path out of Africa: Haiti, the US then the world

Mon, 29 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com )

The AIDS virus entered the United States via Haiti, probably arriving in just one person in about 1969, earlier than previously believed, according to new research.

After the virus, HIV-1, entered the U.S., it flourished and spread worldwide.

Our results show that the strain of virus that spawned the U.S. AIDS epidemic probably arrived in or around 1969. That is earlier than a lot of people had imagined, said senior author Michael Worobey.

The research is the first to definitively pinpoint when and from where HIV-1 entered the United States and shows that most HIV/AIDS viruses in the U.S. descended from a single common ancestor. The actual ancestral HIV entered the U.S. long before the storied Patient Zero, Worobey said.

Haiti was the stepping stone the virus took when it left central Africa and started its sweep around the world, said Worobey, an assistant professor of ecology and evolutionary biology at The University of Arizona in Tucson. Once the virus got to the U.S., then it just moved explosively around the world.

The strain that migrated to the U.S. in 1969, HIV-1 group M subtype B, is the first human immunodeficiency virus discovered. It is the dominant strain of the AIDS virus in most countries outside sub-Saharan Africa. Almost all the viruses in those countries descended from the one that emerged from Haiti, he said.

Worobey and his colleagues figured out when HIV reached the U.S. by conducting genetic analyses of archived blood samples from early AIDS patients.

Learning more about the genetic make-up of the various strains of HIV could help vaccine development, Worobey said.

The scientists' research paper, The emergence of HIV/AIDS in the Americas and beyond, is scheduled for publication in the online Early Online edition of the Proceedings of the National Academy of Sciences the week of October 29.

Worobey's co-authors are M. Thomas P. Gilbert of the University of Copenhagen in Denmark; Andrew Rambaut of the University of Edinburgh in Scotland; Gabriela Wlasiuk of the UA; Thomas J. Spira of the Centers for Disease Control and Prevention in Atlanta, Ga.; and Arthur E. Pitchenik of the University of Miami in Fla. The National Institutes of Health, the David and Lucile Packard Foundation and a University Research Fellowship from The Royal Society funded the research.

Figuring out which path HIV/AIDS took as it began its world travels and when it moved from one country to another has long been a topic of scientific investigation and debate.

Worobey and his colleagues tackled the problem by using archived blood samples from AIDS patients to construct genetic family trees for HIV.

The team analyzed blood from five of the first AIDS patients identified in the U.S., all of whom were recent immigrants from Haiti. The team also analyzed genetic sequences from another 117 AIDS patients from around the world who were infected with subtype B, the virus strain that has spread most widely.

Once all the sequences were assembled, the researchers loaded the data into a computer and used Bayesian statistics to investigate all the family trees that were consistent with the genetic data. The researchers then evaluated all possible HIV family trees to determine how probable a particular family tree is.

For the hypothesis that, from Africa, HIV went to the U.S. first, the probability is 0.003 percent -- virtually nil.

For the hypothesis that HIV went from Africa first to Haiti and then on to the U.S., the probability is 99.8 percent, almost 100 percent.

The analysis also shows that the ancestry of most viruses in the U.S. can be traced back to one common ancestor -- the virus that came from Haiti in about 1969.

Before this study, that had not been nailed down, Worobey said.

The research also reveals that Haiti has a much larger genetic diversity of subtype B than does the U.S.

The U.S., Australia, Europe plus many countries have just a subset of the subtype B diversity you see in Haiti, Worobey said.

The virus moved from Africa to Haiti in about 1966, he said. Haiti has more diversity of HIV than does the U.S. and other countries because the virus has been there longer and had more time to mutate.

The finding helps explain the early observations of a high prevalence of AIDS in Haiti, Worobey said. The virus had simply been there longer.

The main challenge of developing a vaccine against HIV is its tremendous genetic diversity, he said.

Knowing the gamut of diversity within subtype B could be important for effectively developing and testing vaccines that will work in Haiti, Worobey said.

Worobey's next step is following the trail of HIV even further back in time using older archival samples.

HIV patients sicker when seeking care than in the past

Thu, 25 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) It was hoped that as HIV treatment improved and as HIV-related public health initiatives encouraged people to be tested for the disease and seek care, that HIV-infected patients would seek care quickly. Unfortunately, a new study indicates that patients are actually sicker when they begin therapy. The study is published in the November 15 issue of Clinical Infectious Diseases, currently available online.

The study, carried out in Baltimore, MD, from 1990 through 2006, shows that HIV patients beginning HIV therapy have trended toward increasing levels of immunocompromise. This is probably an indicator that people are getting tested for HIV later after they�ve contracted the disease than in the past. Also, people in several key demographic groups are not any quicker now to seek care than they were in the past and some are even taking longer.

HIV is a disease that is most effectively treated if caught early in the course of the illness. Early treatment also helps to limit the spread of the virus from one person to another. For these reasons, HIV services in the United States have evolved over time to encourage people to be tested for HIV and seek treatment if infected.

The researchers, Jeanne Keruly, MS and Richard Moore, MD, of Johns Hopkins University School of Medicine in Baltimore, analyzed data from over 3,300 patients seeking HIV care from the Johns Hopkins HIV service. The data were examined both as a whole and as demographic subsets including gender, race, injecting drug use, men who have sex with men, and heterosexuals. They looked at the amount of time between a patient�s diagnosis of HIV and the time when that person first sought care; and they looked at the patient�s immune status at the time of first care. Ideally, they would have found trends that showed a decrease in the time between diagnosis and treatment and an increase in the immune status.

During the years analyzed, men�and in particular white men and men who have sex with men�did have a trend towards seeking care more quickly after receiving an initial diagnosis of HIV. For all men, the average length between diagnosis and presentation for care was 270 days at the beginning of the study, falling to 183 days by the end.

Women�s times to seek treatment, on the other hand, stayed fairly constant. And, unfortunately, injection drug users had a dramatic increase in the time until treatment, from an average of 378 days at the beginning of the study to 630 days at the conclusion.

People in all but one of the demographic categories had a trend of increasing immunocompromise, an indicator of disease development. The level of immunocompromise was such that the person was at increased risk for a poorer clinical outcome from antiretroviral therapy than if they had presented earlier for care. Over time, patients were increasingly likely to present with AIDS or HIV symptoms. The exception was in the men who have sex with men category.

In light of what appears to have been a poor response to efforts to more rapidly diagnose and treat HIV patients in Maryland, the authors call for new strategies to provide earlier HIV testing and referral into care.

Smoked cannabis proven effective in treating neuropathic pain

Wed, 24 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Smoked cannabis eased pain induced in healthy volunteers, according to a study by researchers at the University of California, San Diego (UCSD) Center for Medical Cannabis Research (CMCR.) However, the researchers found that less may be more.

In the placebo controlled study of 15 subjects, a low dose of cannabis showed no effect, a medium dose provided moderate pain relief, and a high dose increased the pain response. The results suggest a therapeutic window for cannabis analgesia, according to lead researcher Mark Wallace, M.D., professor of anesthesiology at UCSD School of Medicine and Program Director for the UCSD Center for Pain Medicine.

The paper, to be published in the November issue of the journal Anesthesiology, is the second published study out of the CMCR. Headquartered at UCSD, the CMCR is collaboration between UCSD and UC San Francisco that was funded by a state-funded initiative in 1999 to rigorously study the safety and efficacy of medicinal cannabis in treating diseases.

The study used capsaicin, an alkaloid derived from hot chili peppers that is an irritant to the skin, to mimic the type of neuropathic pain experienced by patients with HIV/AIDS, diabetes or shingles � brief, intense pain following by a longer-lasting secondary pain. The subjects were healthy volunteers who inhaled either medical cannabis or a placebo after pain was induced. The marijuana cigarettes were formulated under NIH supervision to contain either zero, two, four or eight percent delta-9-tetrahydrocannabinol (THC.)

�Subjects reported a decrease in pain at the medium dose, and there was also a significant correlation between plasma levels of THC, the active ingredient in cannabis, and decreased pain,� said Igor Grant, M.D., F.R.C.P.(C), professor and Executive Vice-Chair of the Department of Psychiatry, the director of the CMCR. �Interestingly, the analgesic effect wasn�t immediate; it took about 45 minutes for the cannabis to have an impact on the pain,� he said.

The results, showing a medium-dose (4% THC by weight) of cannabis to be an effective analgesic, converged with results from the CMCR�s first published study, a paper by UCSF researcher Donald Abrams, M.D. published in the journal Neurology in February 2007. In that randomized placebo-controlled trial, patients smoking the same dose of cannabis experienced a 34% reduction in HIV-associated sensory neuropathy pain�twice the rate experienced by patients receiving a placebo.

�This study helps to build a case that cannabis does have therapeutic value at a medium-dose level,� said Grant. �It also suggests that higher doses aren�t necessarily better in certain situations � something also observed with other medications, such as antidepressants.�

The researchers stated that more and larger studies need to be conducted to measure the efficacy of cannabis, noting that medical marijuana could play an important role in treating patients who don�t respond well to the usual pain relievers or can�t tolerate drugs such as ibuprofen or opioids used for severe pain.

�The results of this study might help guide others doing clinical research into pain management,� said Wallace.

Fight against HIV needs local scientists, say researchers

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists from developing countries are vitally important in the fight against HIV and they must be given the proper resources to conduct their work, according to a new commentary published today in the journal Nature Immunology.

Researchers from Imperial College London, who are evaluating multiple candidate vaccines designed to prevent HIV, argue that Western governments and funding agencies must commit to sharing technology and expertise with those in the developing world on a long-term basis.

The researchers have been working with local scientists in Uganda and other sites in the developing world to enable large-scale international trials of potential vaccines against HIV. They argue their work shows that it is both feasible and desirable to carry out high-quality trials in developing countries, but that more state-of-the-art laboratories are needed in the developing world to support such trials and enable the roll-out of antiretroviral drugs.

The authors write that people in countries like Uganda wish to take ownership of, or at the very least be equal partners in, efforts to develop treatments for HIV to benefit their population.

�Old fashioned �parachute science� � where scientists from the developed world flew in, bled a few patients, and immediately returned to their country of origin with their samples, are no longer required or acceptable. In-house development and research is an effective and efficient way forward,� said Professor Frances Gotch, one of the commentary�s authors from the Division of Investigative Science at Imperial College.

Uganda is a relative success story in relation to other parts of sub-Saharan Africa in terms of how it has dealt with the spread of HIV, thanks to a National AIDS Control programme, which was established early in the epidemic. Nonetheless, one million people in the country are living with HIV and contributions from the West have been and continue to be crucial in Uganda and elsewhere, say the authors.

Collaborations across sub-Saharan Africa have so far enabled the creation of network of state-of-the-art laboratories, staffed by local scientists and technologists. Cooperation between the Ugandan government and international bodies has enabled the development of research which has led to improved HIV screening and counselling; free mosquito nets and water purification to prevent opportunistic infections; and free testing and treatment for basic infections of danger to those living with AIDS.

�Western governments and funding agencies need to continue to build capacity and train future generations of scientists and doctors on-site in new technologies,� added Professor Gotch. �Countries need resources to maintain and sustain not only the facilities and equipment, but also staff in these countries who are trained and motivated. It is most important to give countries the capacity to train the trainers in their country so that knowledge can be shared and developed there.�

The commentary is part of the Council of Science Editors' global theme issue on poverty and human development, launched today by the National Institutes of Health to coincide with the publication of related research by more than 230 journals worldwide.

Clues to ensuring anti-HIV drugs are taken in Africa

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) DURHAM, N.C. � HIV-infected patients in the African country of Tanzania were more likely to stop taking their medications and to fail treatment if they had to pay for the drugs themselves.

According the results of a new study conducted by Tanzanian physicians and Duke University Medical Center researchers, HIV-infected patients who openly discussed their illness were also more likely to fare better.

�Our findings suggest that efforts to provide free medication to HIV-infected patients and to promote social coping may increase the chances that patients will continue taking their medications and therefore have stronger immune systems and live longer,� said Habib Ramadhani, M.D., physician at the Kilimanjaro Christian Medical Centre and lead author of a paper appearing early online in the journal Clinical Infectious Diseases. Infectious disease specialists from Duke collaborate with the Kilimanjaro medical center physicians at a clinic in Moshi, Tanzania.

The findings of this and other studies in sub-Saharan African countries should help policy makers and physicians figure out how best to direct and manage the increase in the amount of powerful HIV-fighting drugs that are flowing into the continent, the researchers said. This group of drugs, known generally as anti-retroviral therapy, can suppress the levels of virus in the blood to almost non-detectable levels and prolong life.

In order to better understand the barriers that may keep patients in such economically challenged countries from successfully fighting the disease, the researchers studied 150 HIV-infected patients seen at the Moshi clinic, paying particular attention to how well patients were adhering to their medication regimens and how successfully the levels of virus in the blood was responding to the therapy.

About one in six of the patients reported not taking their medications according to schedule, and the patients more likely to have stopped complying were those who had spent a larger proportion of their time on treatment paying for the antiretroviral medicines themselves. These patients typically used their scant resources on other necessities, such as food and shelter, rather than the medicines, researchers said.

They also found that about one in three patients had increases in the level of virus in the blood consistent with treatment failure, and not surprisingly, the patients who were not taking their drugs were more likely to have treatment failure.

�Another quite interesting finding was that being public about their HIV status was associated with suppression of virus,� Ramadhani said. �There still is a substantial stigma associated with HIV in Africa. It is likely that individuals infected with HIV who discussed their disease with friends or family members are likely living in supportive environments that promote adherence.�

The researchers also found that the farther away patients were from the clinic, the less likely they would take their drugs as instructed.

�This study has identified critical factors that affect the success of antiretroviral therapy programs in Africa, and we believe that these findings should be incorporated by policy makers into practice,� said Duke�s John Crump, M.B., Ch.B, who specializes in infectious diseases and international health and is a senior member of the research team. �These drugs, which are known to work, should be free and readily available.

�Structural barriers to care, such as the distance to clinics and especially the burden of patients paying for their medication, must be removed,� Crump continued. �Social coping, including the disclosure of HIV status to people to family and friends leads to better adherence to medication and lower rates of treatment failure.�

According to Michael H., Merson. M.D., director of the Duke Global Health Institute, This study nicely illustrates some of the factors that need to be considered in reducing the health disparities between the haves and have nots throughout the world, and the value of exploring ways to eliminate them through a multidisciplinary lens. Reducing costs, increasing access and lessening stigma are all necessary for providing good AIDS treatment.

Improvement still needed in HIV testing in high-risk groups

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) DURHAM, N.C. � Since 2000, the rates of HIV testing have remained relatively low and constant in the United States, with about one third of Americans ever having had an HIV test, and less than a quarter of the people considered at high risk for contracting the virus that causes AIDS report having been tested in the past year.

The Duke University researchers who conducted an analysis of testing rates argue that while national HIV testing efforts have been expanded to include lower risk populations, there is still untapped potential to increase testing rates among high-risk individuals.

�We found that high-risk groups want to get tested � but their actions don�t match up with their intentions,� said Brian Wells Pence, Ph.D., an infectious diseases epidemiologist at Duke University�s Center for Health Policy and co-author of a study appearing early online in the Archives of Internal Medicine.

The analysis of health surveys of 146,868 Americans showed that those at high risk for HIV, those who were depressed, and those who abused alcohol all demonstrated significant gaps between their intentions to get tested and their actual testing behavior � an observation that did not hold for lower-risk groups.

�Recent policy statements emphasize broadening HIV testing in the general population,� Pence said. �But such efforts should not come at the expense of trying to meet the desire for testing in higher risk groups. The results of our analysis suggest that high-risk groups know they should be tested � so significant potential may still exist to increase testing in such groups by focusing on access. Patients at alcohol and mental health treatment sites, for example, may be receptive to increased testing opportunities.�

People at high risk for contracting AIDS include those who have unprotected sex or who are injection drug abusers.

For their analysis, researchers pooled data collected during six consecutive annual National Health Interview Surveys, beginning in 2000. These detailed federal surveys of more than 35,000 households each year cover a wide variety of topics and are intended to get a �snapshot� of the overall health of the American population. The Duke researchers focused on a particular aspect of the survey results -- the difference between the proportion of individuals reporting an intention to get an HIV test in the coming year and the proportion that had been tested in the past year.

The researchers found that overall, rates of actual testing slightly exceeded rates of planned testing � but the reverse was true among high-risk groups. Specifically, although 27 percent of those at highest risk said they wanted to be tested in the next year, only 11 percent had actually sought out a recent test, Pence said.

�Our analysis suggests that individual and structural barriers keep some individuals, and especially high-risk individuals, from translating their testing intentions into action,� Pence said. �Those who lacked a source of primary health care, for instance, were less likely to act on their intentions to test. The same was true of individuals who reported being depressed or abusing alcohol.�

In a finding that supports the Center for Disease Control and Prevention�s recommendation that HIV testing be included in routine medical care, the Duke team found that about 44 percent of the tests taken during the study period were prompted by encounters with the health care system, such as prenatal care visits or other routine medical appointments. The researchers concluded that the CDC�s efforts to incorporate HIV testing in routine medical care have been successful in making testing more generally available.

The researchers also found that minority women were significantly more likely to get tested than white males.

An estimated 1.1 million Americans are infected with HIV, with about one-quarter of them unaware of their infection. This minority who do not know their status are believed to be responsible for over half of new HIV infections in the United States, making the expansion of HIV testing a top priority for the CDC.

High-risk individuals less likely to follow through on HIV testing plans

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One-fourth of individuals at high risk for contracting HIV report planning to be tested for the virus in the next year, but fewer appear to follow through on that intention than individuals who are at lower risk, according to a report in the October 22 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

About 1.1 million U.S. individuals are affected with the HIV virus, and 24 percent to 27 percent do not know they are infected, according to background information in the article. The HIV epidemic is increasingly affecting groups not perceived as being high-risk, including women, the poor and individuals living in rural areas. �Initiatives to increase the rates of HIV testing, particularly among groups not traditionally perceived as being at high risk, have been advanced as a primary strategy in the effort to combat the HIV epidemic,� the authors write.

Jan Ostermann, Ph.D., M.S., of Duke University, Durham, N.C., and colleagues analyzed data from 146,868 adults age 18 to 64 who were interviewed between 2000 and 2005 as part of the National Health Interview Surveys. Participants were asked whether any of a list of HIV risk factors, such as receiving blood clotting factors for hemophilia or using injection drugs, applied to them. They also reported their HIV testing history and whether they planned on being tested in the next year, in addition to how often they drank alcohol, whether they had symptoms of depression and their sociodemographic information, such as age, education and marital status.

Overall, rates of HIV testing remained approximately the same between 2000 and 2005, with 37 percent of participants reporting being tested in their lifetimes and 10 percent within the past year. Females, minorities and individuals who reported greater risks for HIV were more likely to be tested. However, even among those reporting a medium or high risk for HIV, fewer than 25 percent were tested in the previous year.

In addition, �the difference between planned and actual testing was greater for those with greater HIV risk factors,� the authors write. �Indeed, those with a lifetime HIV risk factor, with medium or high self-perceived HIV risk, and with heavier alcohol consumption were all less likely to actually get tested than to report an intention to get tested.� For example, among those who reported a lifetime risk factor for HIV, 16 percent fewer individuals received a voluntary HIV test than reported planning to get tested, compared with a 5.6 percent deficit between planned and actual testing for those with no risk factors.

�These findings suggest that considerable potential exists to increase testing in higher-risk groups if individual and structural barriers can be identified and addressed,� the authors conclude. �Alcohol and mental health treatment sites, for example, may represent a valuable opportunity to increase testing rates for higher-risk populations who exhibit a marked demand for testing. Although compelling arguments have motivated the current focus on general population testing, such efforts should not come at the expense of ensuring access to and utilization of testing by higher-risk groups.�

HIV is spread most by people with medium levels of HIV in blood, says study

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) People with medium levels of HIV in their blood are likely to contribute most to the spread of the virus, according to new research published today in the journal Proceedings of the National Academy of Sciences.

The study, by researchers from Imperial College London, looked at several groups of HIV-positive people in Europe, the USA and sub-Saharan Africa. It found that those with a high viral load are the most infectious group, but have only limited time to infect others, because they generally progress to AIDS quite quickly.

Viral load - a count of how many viral particles are in a person�s blood � varies hugely between individuals. The higher the viral load, the more infectious a person is but the shorter their life expectancy. As a result, the study found, those with a high viral load do not contribute the most in the long run to the spread of HIV.

Those with a medium viral load are moderately infectious but remain asymptomatic for a period of about six to eight years before progressing to the symptoms of AIDS. This means they can be unaware that they have HIV for a long period of time, during which they can transmit the virus to a number of different sexual partners, and hence contribute most to the epidemic.

Dr D�irdre Hollingsworth, one of the authors of the paper from the Department of Infectious Disease Epidemiology at Imperial College, said: �Just being highly infectious isn�t enough, you have to live long enough to pass the virus on. This long-term view should inform public health policy.�

Despite much recent progress, effective treatment is still not widely available across sub-Saharan Africa, where most infected individuals live. One idea which has been put forward is that treatment should target the most infectious people, with high viral loads, in order to limit transmission. The results of the new study suggest that this would not be an effective plan, as the largest number of new infections is caused by people with medium viral loads.

Those with a medium viral load form the largest, most common group amongst those not receiving treatment. One reason for this could be that the virus has evolved to achieve the optimal balance between infectiousness and virulence, in order to maximise its chances of getting passed on.

Dr William Hanage, another of the authors from the same department at Imperial, commented: �It�s certainly very striking that the viral loads we see most in nature are just right to make sure the virus gets transmitted as much as it can before it kills its host, which is what you would expect from evolution.�

Dr Christophe Fraser, lead author of the study from the Department of Infectious Disease Epidemiology at Imperial College, added: �We now want to see whether the virus has adapted in order to allow it to infect the most people, which seems plausible given the results of our study. This would have serious implications for public health policy, because if it is true then some strategies to prevent transmission could end up making the virus more virulent by accident. While it is too early to sound the alarm, more research to prove or disprove this theory is urgently needed. That is what we are focusing on now.�

UF researchers track genetic journey of HIV from birth to death

Tue, 16 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) GAINESVILLE, Fla. --- University of Florida scientists have discovered how HIV evolves over the course of a person�s lifetime into a more deadly form that heralds the onset of full-blown AIDS. The findings could pave the way for new therapeutic agents that target the virus earlier in the disease process, before it takes a lethal turn, researchers say.

�We were very interested in understanding how the virus mutates from the beginning of the infection until the end,� said Marco Salemi, an assistant professor of pathology, immunology and laboratory medicine in the UF College of Medicine and lead author on the study, which appeared in an online issue of the journal PLoS ONE in September. �Previously, the only thing known was that somehow the HIV population mutates. And as soon as that happens, patients start developing AIDS. But no one knew how and where the population evolved over time.�

To find out, UF researchers began tracking four children born with HIV, studying blood samples taken at birth, throughout life and just after death, when tissues samples were also taken. Using a high-resolution computational technique, they monitored mutations in a protein that helps HIV attach to human cells and then categorized the virus into two groups, R5 and X4. The R5 population is usually present in high numbers during the early stages of infection. But the X4 population enters the scene later, just before HIV gives way to full-blown AIDS. The researchers tracked the viruses in each patient to find out when and where the telltale X4 population first appeared.

�The general dogma has always been that the X4 viruses are more pathogenic than the R5 viruses. And that really isn�t true. People die from the R5 viruses,� said Maureen Goodenow, senior author of the paper and the Stephany W. Holloway university chair for AIDS research in the UF College of Medicine. �But certainly evolution of these X4 viruses is not a good prognostic indicator. So if we could understand the selective pressures that push viruses to develop like that, and the steps involved in the conversion of viruses, then we might be able to set up new targets for drug development.�

Previous studies have relied on cell culture or animal models to follow the virus� mutations over time. The UF researchers are among the first groups to study the progression of HIV in human patients.

As the study revealed new information about the evolution of HIV, UF scientists learned that most viral changes take place in the thymus, a small organ located behind the breastbone that is responsible for immune cell development.

�We found that the late-stage viruses, the X4 viruses, were localized predominantly in the thymus,� Goodenow said. �It says that the thymus is the place where these viruses develop, or at least where they�re localized and replicate.�

The origin of the X4 viruses has puzzled scientists for years. The UF research reveals that the X4 viruses are not present in the body all along, as some scientists had speculated, but rather, that they evolve directly from the R5 population just before the onset of AIDS. The researchers also found that HIV followed a similar path in each child, regardless of variations in the patients� medical histories.

�We�re starting to see what looks like a program of virus development over time. And it doesn�t matter who the person is. And it doesn�t matter what the time scale is,� Goodenow said. �It�s raising the possibility that, in fact, the evolutionary track of the virus is not totally random. There could be a real developmental program that the virus goes through.�

Eight years ago, when the National Institutes of Health-funded study began, pregnant women infected with HIV had few therapeutic options. But recent advances in prenatal drug therapies have substantially decreased the rates of mother-to-child transmission. The Centers for Disease Control and Prevention estimates that less than 2 percent of American mothers currently infected with HIV/AIDS will transmit the viruses to their babies during birth. Without the drugs, about 40 percent of infected mothers would give birth to babies with HIV.

Those therapies may help future children, but they came too late for the subjects enrolled in the study. The children received minimal medication and all developed full-blown AIDS by their first birthdays.

�Their whole virus infection was what we call the natural history,� Goodenow said. �This tells you what happens in the absence of combination antiretroviral therapy.�

The next step, Goodenow said, will be to track the evolution of HIV in adults before and after treatment. The researchers hope their findings will pave the way for new drugs that interfere with the virus� ability to evolve in the thymus.

�This is an excellent study that reveals fine-scale patterns in the evolution and adaptation of HIV during infection,� said Oliver Pybus, a research fellow in the department of zoology at Oxford University. Pybus was part of a team that, three years ago in Science, published descriptions of the high-resolution technique UF researchers used in their study. �For the first time, it shows how the movement of immune cells with the body is linked to the evolutionary behavior of the virus, which in turn determines the clinical outcome of infection.�

Darwin Symposium at Field Museum offers broad overview of his science and its impact

Tue, 16 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) CHICAGO�World-class experts from the United States and Great Britain will speak at The Field Museum for a one-of-a-kind symposium on Charles Darwin and his theory of evolution, which continues to excite the world and direct scientific research 125 years after Darwin�s death.

The free one-day symposium will be held Saturday, November 3, 2007, from 9:00 a.m. to 5:00 p.m. at The Field Museum�s James Simpson Theater. It will cover Darwin and his theory broadly and comprehensively and reveal new directions in cutting-edge research. At the same time, subject matter will be presented in clear terms that museum goers will be able to understand.

�We will be celebrating one of the great scientific revolutions of all time�as well as the person behind it,� said Neil Shubin, Field Museum Provost and Associate Dean for Organismal and Evolutionary Biology at the University of Chicago. �Darwin changed the way we think about our world and our place in it. This symposium is an opportunity to showcase some of the cutting-edge research that is currently underway in the variety of fields that Darwin impacted.�

Shubin will speak at the symposium about the origin of tetrapod limbs. A tetrapod is any vertebrate with four limbs (or four-limbed ancestors). It is a group of animals that includes the human being. Shubin made headlines around the world last year with the discovery of Tiktalik, a fishlike creature with limbs that allowed it to walk on land.

At this time with the theory of evolution under attack in some quarters, the public should strive to better understand Darwin and how his theory of evolution continues to provide a contextual framework for explaining all of life on earth, scientists say. �It is truly amazing that Darwin�s theory continues to hold up under the light of modern genetics and molecular biology,� said Olivier Rieppel, chair of The Field Museum�s Geology Department and Curator of Fossil Amphibians and Reptiles.

Darwin had no knowledge of genes whatsoever, yet some of the best evidence for his theories have come from genetics�a field that did not even exist at his time. Many of the talks will show how various diverse scientific disciplines, from molecular biology to medicine and genetics to paleontology not only support Darwin�s theories but also allow us to understand some of the key events in evolution.

�Darwin is an example of what the best science can do,� Shubin concluded. �A single idea can change the world and offer us new ways to see ourselves. In fact, as we learn more about our genome and those of other creatures, Darwin's theories become ever more relevant.�

The symposium coincides with the popular Darwin exhibition at The Field Museum that covers his life and his science. For information about this exhibition, which runs until January 1, 2008, see

Lack of HIV prevention for male sex workers in the Caribbean could fuel AIDS epidemic

Thu, 11 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) ANN ARBOR, Mich.---Male sex tourists, largely from the United States and Europe, may be fueling an HIV/AIDS epidemic in the Caribbean, and efforts to stop the epidemic will be severely hampered unless HIV prevention dollars are diverted to help male prostitutes, a new study suggests.

Additionally, the study should serve as call to action for the tourism industry to implement HIV/AIDS prevention programs for tourists and tourism employees, said assistant professor Mark Padilla of the University of Michigan School of Public Health.

The Caribbean is second only to sub-Saharan Africa in HIV/AIDS cases. The disease has been described as primarily heterosexual, Padilla said. However, Padilla's book shows that sexual contact between Caribbean male sex workers and male tourists may be a much larger contributor to the HIV/AIDS epidemic there than previously thought.

Currently, prevention dollars in the Caribbean serve primarily heterosexuals, and this particular population of male sex workers who have sex with tourists is largely neglected. That population of male prostitutes grows larger as the traditional, agricultural jobs dry up. Funding comes from a variety of sources: governments, multilateral organizations such as the World Health Organization, and private foundations.

The Caribbean has become increasingly dependent on money from tourism, and young men have fewer options for making a living. Most male sex tourists in the study were from North America and Europe, Padilla said. The local men who served these tourists also had sexual encounters with female tourists, but Padilla's study did not directly examine that issue.

Many men are unemployed from rural areas, and they immigrate to tourism areas, Padilla said. Very few identify themselves as sex workers, and most have other income from tourism. Because of social stigma, these men often do not communicate with female partners about their involvement in sex work, which means the risk for HIV may be high among women.

The problem of why the bisexually behaving men do not come forth and are not reached by prevention programs is complicated, Padilla said. In Latin American culture, homosexuality is so stigmatized that men who engage in homosexual sex for money cannot speak out without becoming social pariahs. Many of them are married, but do not tell their wives about the prostitution or homosexual behavior. Many of these men do not use condoms consistently, especially with female partners, the study found.

Padilla said the tourism industry needs to be held at least partly responsible for providing a safer environment. Many of those tourism companies are based in the United States, he said.

The tourism industry needs to prioritize HIV prevention in any initiative they begin, he said. They should not be able to establish these massive tourism conglomerates without HIV/AIDS prevention and intervention programs.

They need to be aware that they are contributing to a sex economy that they are indirectly supporting, and to take responsibility to provide HIV prevention for these individuals, Padilla said.

Travelers can also lobby the industries directly, Padilla said. You can have an impact on the HIV epidemic simply by stating directly to your travel agency that you prefer a place with HIV prevention as a part of its company strategy. While there is little public information on the HIV prevention efforts of tourism companies, such questions by tourists may lead to greater attention to this issue.

Feline virus, antiviral drug studied to understand drug resistance

Wed, 10 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio �Researchers at Ohio State will spend the next two years testing their theories about just how an AIDS-like virus in cats is able to resist the powerful medicines that are thrown against it.

It's one of the latest efforts at understanding one of the leading problem areas in medicine today -- antimicrobial drug resistance. When bacteria or viruses become resistant to drugs, they become more difficult, or even impossible, to treat.

The project, funded by the National Institute on Drug Abuse, could reveal how some viral infections become able to withstand antiviral medications and even thrive in the presence of some drugs.

If successful, the research might pave the way to smarter, more effective treatments for a host of pathogens that have learned to resist most therapeutic efforts.

The project grew from important discoveries made five years ago as part of a controversial research program investigating the impact of methamphetamine on feline immunodeficiency virus (FIV) � one of only three animal viruses that can be used to mimick HIV (human immunodeficiency virus) infections in humans.

Surprisingly, that project showed that the virus was able reproduce itself 15 times faster when methamphetamine was present.

The work also showed that FIV mutated rapidly to adapt to grow in astrocytes, the dominant cell type within the brain, and that this phenomenon was accelerated by exposure to methamphetamine.

That observation led to an epiphany of sorts, explained Lawrence Mathes, professor of veterinary biosciences and associate dean for research and graduate studies in the College of Veterinary Medicine and principal investigator on the project.

�If the virus becomes drug-resistant as it routinely mutates into this new form, would that drug resistance occur earlier if methamphetamine were present� he asked.

After an initial phase five years ago that used cats as the animal model for the study, research shifted to more refined work with cell cultures of astrocytes grown in the laboratory, focusing on the changes taking place in individual cells. Mathes reasoned that the same mutated form of FIV would probably be present in the brains of infected cats.

He and his colleagues turned to tissue stored from another decade-old unrelated project that looked at how the virus suppressed the animals' immune systems.

�We went back to those tissues and, in fact, found that the same virus mutations we saw in the cultured cell experiments were present in that brain tissue but only after long-term infection,� he said.

The new research grant will use tissue culture methods to look specifically at how the presence of methamphetamine may increase the virus' ability to resist anitiviral drugs, in this case, a powerful AIDS drug called azidothymidine, or AZT.

�We know a lot about AZT, how it works and what mutations it causes in the virus,� he said. The researchers will treat FIV-infected cell cultures with low concentrations of AZT, forcing it to develop a resistance to the drug, repeating the procedure in the presence of methamphetamine.

�We know how long it normally takes the mutation to appear in the virus. We predict that it will appear earlier in cells exposed to both AZT and methamphetamine,� he said.

Mathes said that the first year of the project is focused on continued in vitro studies using both FIV and cat cell lines as well as parallel experiments with HIV in human cell lines.

If the results are promising, the researchers will test the drugs' interactions with the virus in a small study using two dozen cats in the second year.

Stress contributes to range of chronic diseases, Carnegie Mellon psychologist says

Tue, 09 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH -- In a review of the scientific literature on the relationship between stress and disease, Carnegie Mellon University psychologist Sheldon Cohen has found that stress is a contributing factor in human disease, and in particular depression, cardiovascular disease and HIV/AIDS. Cohen�s findings will be published in the Oct. 10 issue of the Journal of the American Medical Association (JAMA). The article was co-authored by Denise Janicki-Deverts of Carnegie Mellon and Gregory E. Miller of the University of British Columbia.

Cohen�s JAMA article was based on a paper commissioned by the Institute of Medicine to examine the evidence that stress influences major diseases. In the JAMA article, the authors consider the behavioral and biological mechanisms through which stress contributes to disease and weigh the results of studies that have examined whether stress plays a role in depression, cardiovascular disease, HIV/AIDS and cancer. Those studies reveal that stress plays a role in triggering or worsening depression and cardiovascular disease and in speeding the progression of HIV/AIDS.

�The majority of people confronted with even traumatic events remain disease-free. Stress increases your risk of developing disease, but it doesn�t mean that just because you are exposed to stressful events, you are going to get sick,� said Cohen, the Robert E. Doherty Professor of Psychology at Carnegie Mellon.

According to the authors, the strongest evidence that stress contributes to disease comes from research on depression, which shows that stress is associated with the onset of depression as well as relapse in people who have recovered from it. Cohen said that particular types of stress are the biggest culprits in depression, namely �social stressors� such as divorce and the death of a loved one. Depression also is common among people who have been diagnosed with a serious illness, suggesting that physical disease itself is a stressful event that can lead to depression. On the other hand, chronic stress -- such as stress experienced daily in the workplace -- contributes to cardiovascular illnesses such as coronary heart disease, a relationship that medical studies have clearly demonstrated, Cohen said.

Results of research on the relationship between stress and HIV/AIDS have been less clear, but since 2000 studies have consistently demonstrated a link between stress and the progression of AIDS. Cohen said that the impact of stress may have become more pronounced in recent years because of the complex and demanding drug regimen that AIDS patients now undergo. He said stress may tax their ability to keep up with their treatment. In the JAMA paper, the authors also note that changes in the autonomic nervous system caused by stress may also contribute to disease progression by influencing the replication of the HIV virus.

�Individuals differ with regard to rate of progression through the successive phases of HIV infection. Some remain asymptomatic for extended periods and respond well to medical treatment, whereas others progress rapidly to AIDS onset, and suffer numerous complications and opportunistic infections. Stress may account for some of this variability in HIV progression,� the authors write.

Exactly how stress causes and contributes to disease is a question of particular interest to researchers. Cohen said there are two likely pathways. One is behavioral -- people under stress sleep poorly and are less likely to exercise; they adopt poor eating habits, smoke more and don�t comply with medical treatment. Stress also triggers a response by the body�s endocrine systems, which release hormones that influence multiple other biological systems, including the immune system.

�Effects of stress on regulation of immune and inflammatory processes have the potential to influence depression, infectious, autoimmune, and coronary artery disease, and at least some (e.g., viral) cancers,� the authors write.

Studies on the role of stress in cancer have not been consistent in their results. Researchers who study the influence of stress on the progression of cancer face many hurdles, according to Cohen and his colleagues. Cancer can go undiagnosed for a long time, and its progression is difficult to measure with much precision. There are many types of cancers, and it is possible that stress only influences those facilitated by sustained hormonal response and impairments in immunity.

�We will need additional studies across a broader range of cancers before we can fairly evaluate the role of stress in cancer,� Cohen said.

NIH grant supports UCSF research exploring early HIV infection

Mon, 08 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A team led by researchers at the UCSF Positive Health Program has been named to receive $15 million over five years to expand understanding of the complex interactions between HIV and the immune systems of newly infected patients following HIV transmission.

The grant is being awarded by the National Institute of Allergy and Infectious Diseases, an arm of the National Institutes of Health.

�The program will provide an important platform for innovative research into HIV transmission and early infection in patients and aims to provide new clues for developing a vaccine and improving therapeutic outcomes,� said the grant�s primary investigator, Frederick Hecht, MD, professor of medicine at the UCSF Positive Health Program at San Francisco General Hospital Medical Center.

The research will be based on two clinical cohorts of recently infected patients: the

�The inclusion of the Brazil cohort allows us to look at two HIV subtypes simultaneously. Subtype C predominates in Sub-Saharan Africa and subtype B predominates in North America, though both are common in Southern Brazil. This provides us with a natural research study for understanding competing HIV subtypes,� said Hecht.

The overall grant aims to understand the viral and host factors that favor or block HIV transmission on a biological level and the factors that favor good control of early HIV infection by newly infected patients. The program is composed of four projects.

One project, led by Hecht, will focus on the transmission and persistence of two types of HIV resistance mutations. Some are caused by infection with HIV variants that have resistance mutations caused by exposure to antiretrovirals. Understanding how easily these mutations occur and how long they persist is important for long-term forecasting of the effectiveness of antiretroviral regimens in populations.

The other types of resistance mutations are those that allow the virus to escape an infected patient�s specific T-cell immune responses. HIV mutates constantly, thereby escaping attack from the body�s targeted T-cell defenses that are meant to kill the virus, and eventually eludes effective control in most individuals. Understanding this process could assist in vaccine development.

A second project, led by Steven Deeks, MD, of the Positive Health Program, examines properties of the outside of the HIV virus�the envelope�and how they influence HIV transmission and evolve in a newly infected individual after transmission. These envelope properties determine which cells most easily will succumb to infection with the virus. In addition, the envelope properties of HIV may affect the virus�s capacity to damage the immune system and determine how readily it is transmitted.

A third project, led by the UCSF-affiliated Gladstone Institute of Virology and Immunology�s Robert Grant, MD, MPH, is focused on superinfection, which is infection with a second HIV virus on top of a preexisting infection. The project will study how readily this occurs in early HIV infection�which appears to be the most vulnerable period for superinfection�and what factors may prevent it.

The fourth project, led by Douglas Nixon, MD, PhD, of the UCSF Division of Experimental Medicine, tests whether new immune responses, following HIV transmission to a newly infected patient, help to reverse some of the mutations that allowed the virus to escape immune responses in the HIV-individual who transmitted the virus.

How Candida albicans transforms from its normally benign form into life-threatening form

Thu, 04 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the Agency for Science, Technology and Research's (A*STAR) Institute of Molecular and Cell Biology (IMCB) have discovered new molecular mechanisms that provide a more detailed understanding of how the normally benign Dr. Jekyll-like fungus known as Candida albicans transforms into a serious and often life-threatening Mr. Hyde-like form.

C. albicans can cause serious and potentially life-threatening infections in the mouth, blood and other tissues of people who are undergoing cancer chemotherapy or radiation treatments, or who have developed AIDS or other diseases that damage the immunity of the individual.

In two separate papers published last month in Developmental Cell and in August in the EMBO journal, the team of scientists led by Wang Yue, principal investigator at IMCB, have managed to reveal previously unknown mechanisms which are responsible for causing the infectious phase of C. albicans.

The fungus starts its 'attack' on a patient by changing its oval shape into a filamentous form, which has thin, threadlike appendages emerging from the cell body. Wang's team, who has been studying C. albicans for more than seven years, was responsible for identifying the master controller protein called Hgc1 in 20041.

This controller functions like a regulator and tells the fungus when to start the transformation from the harmless oval shape to the infectious filamentous form.

One question remained, however - how does it activate the cellular machineries that determine the fungal cell shape? said Wang.

Wang's team found the answer to this question in two proteins called Rga2 and Cdc11. They discovered that they each function like a switch on two different cellular machineries that normally determines cell shape. The master regulator Hgc1 acts like the 'finger' that flips the switches to start the infection process, said Wang.

Our findings have uncovered detailed molecular mechanisms which define how these two proteins interact with the master 'controller' to cause infections. Thishas opened new opportunities for us to investigate further into a new range of therapeutic targets for fungal infections, explained Wang.

In the same issue of Developmental Cell, the team's work was given an expert mention by a leading C. albicans researcher, Dr. Peter Sudbery, stating its importance in bringing awareness of the cellular processes that is necessary for C. albicans to transform to its infectious state.

In addition, the new knowledge of the detailed interaction of these proteins with other cellular machineries has also revealed critical information on how cells in general determine their shape, a fundamental question in biology as Rga2 and Cdc11 are also found in nearly all eukaryotic organisms.

Largely due to the AIDS pandemic in the last 25 years, the once nearly harmless and commensal fungus Candida albicans has become one of the most prevalent microbial pathogens in AIDS patients, causing life-threatening infections with high death rate, especially in infected children.

Second pathway behind HIV-associated immune system dysfunction identified

Sun, 30 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH) may have discovered a second molecular �switch� responsible for turning off the immune system�s response against HIV. Last year members of the same team identified a molecule called PD-1 that suppresses the activity of HIV-specific CD8 T cells that should destroy virus-infected cells. Now the researchers describe how a regulatory protein called CTLA-4 inhibits the action of HIV-specific CD4 T cells that control the overall response against the virus. The report will appear in the journal Nature Immunology and is receiving early online release.

�We�ve shown that a known regulator of the immune system, CTLA-4, is present in elevated levels on the virus-specific CD4 cells that should be managing the body�s response against HIV, says Daniel Kaufmann, MD, of PARC and the MGH Infectious Disease Unit, a co-first author of the paper. �We also found that CTLA-4 expression rises as HIV infection progresses and that the molecule switches off CD4 cell function in a way that appears to be reversible.�

Expression of the CTLA-4 protein is known to be elevated on activated T cells, those that have encountered a pathogen and are multiplying rapidly to mount an immune response. Studies in cancer patients have shown that the molecule serves to dampen the immune response, and some preliminary investigations in animals and humans have suggested a potential role in HIV infection. The current study was designed to examine how CTLA-4 may be involved in the dysfunction of HIV-specific T cells that leads to the immune-system breakdown of AIDS.

The researchers first found that CTLA-4 was overexpressed on the HIV-specific CD4 T cells of infected individuals who had not yet received antiviral treatment. Levels were highest in those with symptoms of acute infection and second highest in chronically infected participants. CTLA-4 expression was lowest among a group of participants whose immune systems were naturally able to suppress HIV replication without antiviral medications � �elite controllers� in whom viral levels are too low to be detected.

Elevated CTLA-4 expression also correlated with signs of disease progression � increased viral load and reduced overall CD4 count. While antiviral treatment caused viral loads to drop significantly after treatment began, it resulted in only modest and slow drops in CTLA-4 expression. In vitro tests of the effects of blocking the CTLA-4 molecule improved the function of HIV-specific CD4 cells. Comparing the effects of blocking CTLA-4 with those of blocking PD-1 or both molecules produced functional improvements that varied considerably between participants, signifying a complex relationship between the pathways controlled by the two molecules.

�Both of these pathways contribute to dysfunction of HIV-specific T cells and both may be considered targets for therapeutic intervention. But since their mechanisms are so complicated, further study is needed before clinical trials can be planned,� says Kaufmann, an instructor in Medicine at Harvard Medical School (HMS).

�Understanding why the immune system fails to control HIV is essential for development of vaccines and new therapies� said Bruce Walker, MD, director of PARC-MGH and senior author of the study. �These studies suggest that the immune system is turning itself off prematurely in HIV-infected persons, and the big challenge now is to figure out if we can turn it back on, getting it to do what it is supposed to do, without causing collateral damage in the process.� Walker is a professor of Medicine at HMS and a Howard Hughes Medical Institute (HHMI) investigator.

Pregnancy may slow -- not accelerate -- progression to AIDS

Wed, 19 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new study may help put to rest fears that pregnancy accelerates progression to full-blown AIDS in women with HIV receiving antiretroviral therapy. The study, published in the October 1st issue of the Journal of Infectious Diseases and now available online, revealed that pregnancy may, in fact, slow disease progression in these women.

Before the advent of highly active antiretroviral therapy (HAART), many women with HIV infection or AIDS were told that becoming pregnant would be unwise because there was thought to be a 25 percent risk of transmitting the virus to the child and that the effects of pregnancy on disease progression were unclear. It is now clear that the use of HAART in pregnancy can reduce the HIV transmission to the newborn to approximately 1 percent, but the effects of pregnancy on the HIV-infected woman remain unknown.

To determine the effects of pregnancy on HIV disease progression in the HAART era, Timothy R. Sterling, MD, and colleagues at Vanderbilt University performed an observational study of HIV-infected women between 1997 and 2004. Disease progression was defined as experiencing an AIDS-defining event such as Kaposi�s sarcoma, Pneumocystis carinii pneumonia, or Candida fungal infection of the esophagus; or death. Of the 759 women studied, 71 percent (540) were receiving HAART. Eighteen percent (139) of women studied had one or more pregnancy during this study.

Based on the results of studies conducted before HAART, researchers had expected there might be no difference in HIV disease progression between pregnant and non-pregnant women. What Sterling and colleagues found was that women who became pregnant actually had a lower risk of HIV disease progression and were healthier than women who did not become pregnant. Women experienced a lower risk of disease progression both before and after pregnancy. This may be a result of the healthier immune status of women who become pregnant and/or a beneficial interaction between pregnancy and HAART.

Although the pregnant women in the study were younger than the non-pregnant women, had higher initial CD4+ lymphocyte counts (white blood cells that are attacked by HIV), and a smaller amount of HIV RNA in their plasma, their risk of disease progression remained lower even after factoring in these differences. Nor did it matter that the pregnant women also were more likely to receive HAART and more likely to attend clinic appointments.

Additionally, women with multiple pregnancies during follow-up tended to have a lower risk of disease progression than did women with only one pregnancy. Sterling notes, �This apparent dose-response relationship supports a possible protective effect of pregnancy on disease progression. Pregnancy is associated with a complex set of immunological changes during the gestation period, which may provide additional benefit to the mother�s health.�

In an accompanying editorial, Kathryn Anastos, MD, of the Albert Einstein College of Medicine emphasized that although understanding of this complexity is not complete,

Dr. Sterling�s study gives hope that correlative studies of the immune response to pregnancy and the influence of pregnancy on HIV disease may help to provide the needed information.

Dr. Anastos suggested that this information may be of particular significance to women in resource-limited communities, who generally bear more children than do those in higher-resource communities. She noted that �women can now have greater confidence that in addition to protecting their children from [mother-to-child transmission of HIV] with HAART, their own health will not be compromised by pregnancy, which would place their children at long-term risk�the findings by Sterling and coworkers suggest that at least for HIV disease progression, the odds may be in their favor.�

NIH selects Weill Cornell Medical College to lead new NYC translational research collaboration

Wed, 19 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Sept. 18, 2007) -- Weill Cornell Medical College has been selected by the National Center for Research Resources (NCRR), of the National Institutes of Health (NIH), to establish and lead a new Clinical and Translational Science Center (CTSC), creating an ambitious and innovative network for biomedical collaboration on New York's Upper East Side. The Center's goal is to facilitate new collaborative research studies that quickly and effectively result in new patient treatments and preventive interventions.

Funded through a prestigious $49 million Clinical and Translational Science Award (CTSA) -- the largest federal grant ever awarded to Weill Cornell, the CTSC will consist of a unique multidisciplinary collaboration between a diverse group of institutions. Led by Weill Cornell Medical College and Weill Cornell Graduate School of Medical Sciences, the new Center also will encompass the Cornell University Cooperative Extension in New York City (CUCE-NYC); NewYork-Presbyterian Hospital/Weill Cornell Medical Center; Memorial Sloan-Kettering Cancer Center (MSKCC); Hospital for Special Surgery (HSS); Hunter College School of Nursing; The Center for Study of Gene Structure and Function of Hunter College, City University of New York; and an additional six Weill Cornell�affiliated hospitals.

There is a pressing need for broad-based multidisciplinary collaborations that can fulfill the incredible promise of recent research advances in areas like genetics and bioinformatics, and efficiently translate them into real-world interventions that benefit the community, says Dr. David Skorton, president of Cornell University and professor of medicine and medicine in pediatrics at Weill Cornell Medical College. As it strives to meet this challenge, the new Clinical and Translational Science Center will also be an integral component of Cornell's commitment to interdisciplinary and inter-institutional collaboration.

We are honored to be selected as the lead institution for this new biomedical complex, and look forward to working with our neighboring institutions to forge new and far-reaching collaborations in order to meet the government's mandate to energize and transform clinical and translational science, says Dr. Antonio M. Gotto Jr., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College. Another key benefit of this program will be its role in helping educate the next generation of researchers trained in the complexities of translating research discoveries into clinical trials and ultimately into practice.

Weill Cornell Medical College is already engaged in numerous ongoing multi-institutional collaborations with members of the Clinical and Translational Science Center -- including Cornell University, Memorial Sloan-Kettering Cancer Center, Hospital for Special Surgery and Hunter College.

The Clinical and Translational Science Center will also take creative approaches to translational research, developing and improving tools for analyzing research data and managing research studies, says Dr. David Hajjar, senior executive vice dean and executive vice provost of Weill Cornell Medical College, dean of the Weill Cornell Graduate School of Medical Sciences, and the Frank H.T. Rhodes Distinguished Professor of Cardiovascular Biology and Genetics. A new Biomedical Research Building, already under development, at Weill Cornell will eventually serve as the hub for this new effort.

This is the largest federal grant ever awarded to this Medical College; and what is truly noteworthy is the reality of several public and private, world-class institutions working in teams across disciplines to promote translational research, says Dr. Julianne Imperato-McGinley, the Center's principal investigator and program director. And, all important innovations will be shared by virtue of our active participation on national CTSA steering committees.

An accomplished clinical and translational researcher with more than 25 years of NIH funding, Dr. Imperato-McGinley will also be named the associate dean for educational training and translational research at Weill Cornell. In addition, she is the Abby Rockefeller Mauz� Distinguished Professor of Medicine in Endocrinology, Diabetes and Metabolism.

Together with our collaborator-institutions, we will work toward moving translational research from bench to bedside to community, continues Dr. Imperato-McGinley. Furthermore, in a process of circular innovation, lessons learned in the community will then be the basis for new research efforts.

An extensive community outreach program, especially for ethnically diverse medically underserved areas, will be an important component of the CTSC initiative. Member institutions, particularly the Cornell University Cooperative Extension, have existing partnerships with key community organizations.

The initiative will target the full range of clinical areas, among them -- cancer, diabetes, AIDS, cardiovascular disease, women's health, reproductive medicine, geriatrics, psychiatry, Alzheimer's disease, kidney disease, obesity, multiple sclerosis, neuromuscular disorders, trauma and burns.

Neighboring institutions will contribute significantly to the CTSC: The Hospital for Special Surgery -- one of the most renowned orthopedic hospitals in the U.S. and a leader in investigating musculoskeletal and autoimmune diseases -- is one of two medical institutions designated by NIH as a Core Center for Skeletal Integrity. Memorial Sloan-Kettering Cancer Center represents one of the world's premier cancer centers where state-of-the-art basic science research flourishes side-by-side with clinical investigation and treatment at Memorial Hospital. Cornell University Cooperative Extension has been engaged in research addressing the needs of a changing New York for over 50 years, and will remain a significant linchpin for community outreach. Hunter College's Gene Center, funded by the Research Center for Minority Institutions Program of NCRR, recruits and nurtures minority talent and has established an effective electronic network with minority scientists nationwide. Hunter College School of Nursing, training nurses from a diverse urban population, participates in community outreach and education in underserved areas.

Many of our ongoing research projects already address AIDS, cancer, neurodegenerative diseases and complaint behavior -- all important aspects of clinical translational research. The CTSA will create synergistic programs among these neighboring institutions and complement the efforts of President Jennifer J. Raab to build a new science building at Hunter College, says Dr. Robert Dottin, director of Hunter's Gene Center.

The CTSA initiative grew out of the NIH commitment to re-engineer the clinical research enterprise, one of the key objectives of the NIH Roadmap for Medical Research. Total funding for these new awards will be approximately $577 million over a five-year budget period.

New antibiotic drug combo to speed up treatment of tuberculosis

Tue, 18 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A team of tuberculosis (TB) experts at Johns Hopkins and in Brazil have evidence that substituting the antibiotic moxifloxacin in the regimen of drugs used to treat the highly contagious form of lung disease could dramatically shorten the time needed to cure the illness from six months to four.

Adding moxifloxacin to a standard combination of other antibiotics increased by 17 percent the number of patients who cleared active infections from their lungs (raising cure rates from 68 percent to 85 percent), after just two months of therapy, and when compared to patients taking the standard combination with another, older antibiotic, ethambutol.

�This is the most compelling evidence in nearly 25 years that a novel antibiotic drug combination works better than the current gold standard at curing active TB infection,� says study senior author Richard E. Chaisson, M.D., a professor of medicine, epidemiology and international health at The Johns Hopkins University School of Medicine and founding director of its Center for Tuberculosis Research. Chaisson will present his team�s findings Sept. 18 in Chicago at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

�Beyond the obvious value of healing patients more quickly, a shorter treatment time could also cut down on transmission of the disease to others and make it easier for health care workers worldwide, who are overwhelmed by large numbers of patients, to treat more people and to treat them faster,� says Chaisson, who started the study in 2003.

He notes that worldwide, each year, nearly 9 million new cases of TB are diagnosed, and more than one and a half million people die from the disease, caused by Mycobacterium tuberculosis.

TB also remains the leading cause of death worldwide among those with HIV and AIDS and is epidemic in developing countries with the highest HIV-infection rates.

The new study of more than 170 men and women in Rio de Janeiro, Brazil � all with active TB � showed that combination drug therapy with moxifloxacin was more potent than combination therapy with an older, more traditional anti-TB drug, ethambutol. Symptoms of active TB include fever, cough, night sweats and weight loss.

After two months of combination therapy, cultured sputum samples from patients taking moxifloxacin were significantly less likely to grow TB bacteria than samples from those on traditional ethambutol therapy. The time to clear the infectious organism from sputum was also significantly shorter in the moxifloxacin group.

Conventional TB therapy prescribes a mix of antibiotics, typically four, given in view of a caregiver and taken together for six months. Commonly known by its acronym DOTS, short for Directly Observed Therapy Short-Course, the treatment cures on average 95 percent of patients who finish taking their medications as originally prescribed.

But experts say the lengthy treatment period has proven a problem for patients, who sometimes miss taking their drugs on time, minimizing the therapy�s effectiveness and increasing the risk that drug-resistant strains will develop.

History, says Chaisson, demonstrates that shorter regimens boost drug compliance and cure rates, often by as much as 50 percent. In the 1950s, TB treatment lasted from 18 to 24 months, and nearly a quarter of patients failed to complete therapy. It was not until new drugs appeared in the 1970s and 1980s, when treatment times were shortened to an average of six months, that cure rates shot up.

In the latest study, all participants were given a standard combination of three antibiotic pills � isoniazid, rifampin, and pyrazinaminde � and then randomly assigned to receive a fourth pill, either moxifloxacin or ethambutol. Moxifloxacin, approved for use in the United States since 1999 as a treatment for pneumonia, is not currently approved as a treatment for TB. However, ethambutol has been approved to treat TB since 1962.

The three combination drugs, which must be taken several times daily for six to eight months, have all been widely used to treat TB disease for decades: isoniazid (since 1952), rifampin (1968) and pyrazinamide (1954).

�It was remarkable to see just how potent moxifloxacin was,� says Chaisson. After just two weeks of therapy with moxifloxacin, 21 percent of the sputum samples were negative and cleared of visible disease, while in the ethambutol study group, it was just 3 percent. After four weeks, the gap widened to 51 percent and 29 percent, respectively.

Chaisson says substituting moxifloxacin for one of the key ingredients in DOTS could also make treatment far less costly overall, allowing TB programs to expand their coverage. The medication currently costs $10 per day for short-term use, but the researcher says the drug�s manufacturer, Bayer Healthcare AG, has promised to make the drug available at affordable prices in poor countries should it gain approval for use in TB.

Chaisson and his team next plan to investigate a potentially even more potent drug combination that includes traditional DOTS drugs with yet another substitution, rifapentine in place of rifampin. Rifapentine became available in the United States in 1998 and scientists say it is more effective against drug-resistant strains of TB.

Chaisson and colleagues conducted their research with funding from the U.S. Food and Drug Administration�s Office of Orphan Product Development. The study was part of a series of studies on moxifloxacin that are being coordinated by the nonprofit Global Alliance for TB Drug Development (GATB) in collaboration with Bayer.

The GATB estimates that 1 billion people worldwide will be infected with tuberculosis by the year 2020, of whom 200 million will fall ill and 35 million will die.

As part of the research program, Bayer donated supplies of moxifloxacin.

Anthony S. Fauci awarded Lasker Award for Public Service

Tue, 18 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), has been awarded the 2007 Mary Woodard Lasker Award for Public Service for his role in developing two major U.S. public health programs, in AIDS and biodefense. The award will be presented on Friday, September 28th during a luncheon ceremony in New York City.

Dr. Fauci is honored for his role in helping develop the President�s Emergency Plan for AIDS Relief (PEPFAR), the largest public health program in history devoted to a single disease, as well as Project Bioshield, designed to accelerate the research, development, purchase and availability of medical countermeasures against the effects of biological, chemical, radiological and nuclear agents.

�In nearly four decades of service to NIH, Tony Fauci has made innumerable scientific contributions that have improved the health of millions of people in this country and abroad,� says NIH Director Elias A. Zerhouni, M.D. �As a clinician, researcher, and scientific leader, Dr. Fauci has channeled his intellect, compassion, and vision into discoveries and research programs that have transformed medicine and public health.�

Earlier this year, Dr. Fauci received two other major honors: the George M. Kober Medal of the Association of American Physicians for his work in clinical medicine, and the National Medal of Science, for his research into the pathogenesis of human immunodeficiency virus (HIV) disease.

Dr. Zerhouni adds, �It is fitting to have Tony recognized with a �trifecta� of awards related to the three fundamental NIH missions: basic research, clinical research, and public service. It is hard to think of anyone more deserving of this award.�

Dr. Fauci�s tenure as NIAID director began in 1984. For nearly 23 years, he has overseen the extensive NIAID research portfolio of basic and applied research to prevent, diagnose and treat infectious and immunologic diseases. The NIAID budget for fiscal year 2007 is approximately $4.4 billion. He has advised several administrations on global HIV/AIDS issues and other emerging disease threats. These issues have also been the subject of his numerous congressional testimonies and briefings.

�It is a remarkable privilege as a physician/scientist to be given the opportunity to help formulate policies and programs that protect and improve global health,� says Dr. Fauci. �I am fortunate to have been in position to help bridge the gap between the biomedical research and policymaking communities, and to assist our leaders in developing programs predicated on the scientific advances made by NIH, our sister agencies within the Department of Health and Human Services, and our many collaborators worldwide.�

In addition to Dr. Fauci�s Lasker award, the 2007 Lasker Award for Basic Medical Research honors long-time NIAID grantee Ralph M. Steinman of Rockefeller University for his discovery of dendritic cells, immune system cells that trigger other components of the immune system to thwart microbial invaders. Further information about the awards and their recipients is available at

The Lasker Awards were first presented in 1946, and are administered by the Albert and Mary Lasker Foundation. The late Mary Woodard Lasker is widely recognized for her singular contribution to the growth of the National Institutes of Health and her unflagging commitment to government funding of medical research in the hope of curing diseases. Her support for medical research spanned five decades, during which she was the nation�s foremost citizen-activist on behalf of medical science.

�It remains critical that the medical and public health communities channel the spirit of Mary Lasker and argue cogently for medical research, and for adequate attention and sustained support for the delivery of the fruits of that research to the people who need them most,� Dr. Fauci notes in an invited commentary in the journal Nature Medicine, available online at

Global Health Project targets reducing AIDS among India's adolescents

Wed, 12 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Tampa, FL (Sept. 12, 2007) -- The University of South Florida�s global health initiative to help India build an infrastructure to fight AIDS has been strengthened with a $1.36-million research training grant from the National Institutes of Health.

USF Health received the five-year grant Sept. 11 from the NIH�s Fogarty International Center to create an interdisciplinary training program focused on the biomedical, behavioral, cultural and ethical aspects of detecting, treating and preventing HIV/AIDS among adolescents in India. USF will partner with Vadodara Medical College in Gujarat, India, to teach Indian physicians, scientists, nurses, and other health professionals how to conduct and evaluate community-based HIV clinical studies for this vulnerable population.

�This program represents another exciting opportunity for USF to shine in the international health arena and to broaden the scope of our HIV research and training partnerships in India,� said USF pediatrician Dr. Patricia Emmanuel, principal investigator for the project. �It will enhance new knowledge in the area of adolescent health and benefit USF and the local communities in India.�

India ranks second worldwide, following South Africa, in the number of HIV and AIDS cases. In some places in India, half of all new HIV infections occur in adolescents and young adults. Young people are at greater risk for HIV for several reasons, including girls� increased biological susceptibility and a tendency for risky behaviors like unprotected sex and IV drug use, Emmanuel said.

India has made some significant inroads in committing resources to the pressing public health problem of AIDS. But, a recent article in the New England Journal of Medicine reports that to curb the spread of the HIV epidemic, the developing nation must meet several challenges, including increasing the number of patients treated, improving the monitoring of therapy, caring for patients with tuberculosis coinfection, and reducing the stigma and discrimination associated with AIDS.

�We expect to train more home-grown investigators who can confront these barriers by addressing research questions specific to the HIV epidemic in India,� Emmanuel said.

The new grant � the latest of three NIH Fogarty International awards to USF faculty -- was spearheaded by USF Health�s Signature Interdisciplinary Program in Allergy, Immunology and Infectious Disease (SPAIID) and the USF-India Center for Health, HIV/AIDS Research and Training (CHART-India). Emmanuel will work with co-principal investigators Dr. Shyam Mohapatra and Dr. Eknath Naik.

The grant will expand the existing HIV infrastructure built by CHART-India. Since 1999, USF medical and public health faculty have established several CHART centers across India to care for people with HIV/AIDS, train staff and conduct research.

The Fogarty project will draw upon the expertise of USF�s nationally-recognized Tampa Bay Adolescent Medicine Trials Unit. The unit, directed by Emmanuel, is one of 15 NIH-funded clinical sites across the country providing comprehensive services to HIV-infected adolescents. Emmanuel oversees a large team of researchers and clinicians who work with both adolescents and children -- educating youth at high risk for HIV in an effort to prevent AIDS, offering new treatments, and evaluating barriers to clinical trial enrollment and retention.

�This prestigious grant is a national recognition of our strategic efforts to create an effective network for the globalization of translational and clinical research,� said Dr. Abdul S. Rao, senior associate vice president for USF Health. �It also underscores the efforts of our interdisciplinary signature program in allergy, immunology and infectious diseases, which was established last year to facilitate such activities.�

Personal chaos in HIV patients' lives may be a barrier to regular medical care, UCLA Study Shows

Tue, 11 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Unstable and unpredictable lifestyles are significant factors in determining access to health care among low-income HIV-positive people, a new UCLA study has found.

The study, to be published in the September issue of the Journal of General Internal Medicine, found that when HIV patients lead chaotic lives � meaning they are disorganized or experience too many unexpected events � that chaos can act as a barrier to regular medical care. The researchers also developed a new scale to gauge the level of chaos in an adult�s life.

The findings suggest a possible new alternative to help ensure that low-income patients get the care they need, said the study�s lead author, Dr. Mitchell Wong, an assistant professor of general internal medicine and health services research at the David Geffen School of Medicine at UCLA.

�Many people have barriers to care, such as problems with transportation, housing, child care and health insurance. Traditionally, we look to solve these problems with case managers who can help reduce these barriers,� Wong said. �But there�s a whole potential other mechanism which might be happening � that people are just having trouble managing and organizing their lives. I think many of us take for granted the support mechanisms that we have, but many people who are living in poverty don�t have that support network. They don�t have that buffer zone to cope with the unexpected things. Perhaps enhancing stability and organization in people�s lives can also help them get the regular care that they need.�

Some 220 low-income HIV-positive patients participated in the study. Of those, 45 percent were African American, 40 percent were Latino and 20 percent were women. About one-third did not graduate from high school, approximately 75 percent had a history of homelessness and half had used drugs in the previous 30 days. In addition, 45 percent were uninsured and 75 percent had one or more unmet social-service need. In the six months prior to the study, 83 percent had seen a physician for HIV care at least twice, 46 percent missed two or more visits, and one-third had gone to a hospital emergency room at least once.

In developing the new scale to measure chaos in adults� lives, the researchers took as their model the 15-item Confusion, Hubbub, and Order Scale (CHAOS), designed for parents to assess chaos affecting children�s home lives. The researchers changed some questions in the CHAOS scale to reflect a person�s life in general and whittled the assessment down to six simple statements designed to key in on the level of chaos in patients� lives. These statements had a five-point response ranging from �strongly agree� to �strongly disagree.�

The statements were:

Decline in blood platelet count associated with increased risk of HIV-related dementia

Mon, 10 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) HIV patients with declining platelet counts appear to be at increased risk for HIV�associated dementia, according to a report in the September issue of Archives of Neurology, one of the JAMA/Archives journals.

�Human immunodeficiency virus�associated dementia (HIV-D) is a syndrome encompassing a spectrum of cognitive, behavioral and motor deficits that usually has an insidious onset and a chronic progressive course,� the authors write as background information in the article. Therapies leading to longer life for HIV patients have paradoxically increased the prevalence of this condition. Identifying biological markers for the development of HIV�associated dementia is critical both for diagnosing the disorder and for understanding its underlying mechanisms.

Lynn M. Wachtman, D.V.M., M.P.H., of Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, and colleagues studied 396 patients with advanced HIV who were recruited for this prospective study between 1998 and 2003. Participants were examined every six months and completed mental and physical evaluations. Blood samples were also collected and assessed for platelet count (the number of clotting cells in the blood), hemoglobin levels, CD4 lymphocyte count (a measure of certain types of white blood cells, which reflects the state of the immune system) and plasma HIV RNA levels (which indicate the amount of �viral load,� and predict HIV progression).

After a median (midpoint) follow-up of 31.1 months, 40 participants developed HIV�associated dementia. A decline in platelet count from baseline was associated with the development of dementia within six to 12 months. �Those HIV-infected individuals with a decline in platelets from baseline values at this lagged time point had a two-fold increased risk of dementia� in several different analyses, the authors write. The specific timing of the association indicates that the levels of circulating platelets fluctuate as HIV�associated dementia develops, they note.

�Further analyses indicated that decline from baseline platelet levels was associated with a five- to six-fold increased risk of dementia during the first two years of follow-up, but it was not associated with an increased risk of dementia after two years,� the authors continue. �It is possible that individuals who do not progress rapidly to neurologic compromise differ in respect to immune activation, treatment adherence or virologic control relative to those who develop dementia more rapidly.�

�Because CD4 cell counts and HIV RNA levels have proven not to be predictive of HIV�associated dementia, it is important to investigate alternative serum and hematologic markers,� the authors conclude. �Should these markers be routinely measured in a clinical setting, such as platelet counts, they may prove useful for patient management. This study identifies a significant association between platelet decline and incident HIV�associated dementia.� Further study of platelet levels during HIV�associated dementia may lead both to a specific marker for the development of HIV�associated dementia and a better understanding of how the disease develops.

(Arch Neurol. 2007;64(9):1264-1272. Available pre-embargo to the media at

Scripps Research scientists shed new light on how antibodies fight HIV

Thu, 06 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) By furthering scientists� understanding of the molecular mechanisms that separate the minority of successful HIV antibodies from the majority of ineffective antibodies, the work may have implications for future attempts to design an HIV vaccine.

The study was published on September 6, 2007, in the journal Nature.

�This study is part of the effort to understand how protection against HIV occurs,� says Dennis Burton, a professor at The Scripps Research Institute. �If we really understand this, then we can design tailor-made vaccines in a way that has never been done before.�

Although vaccines have long been used with great success to prevent diseases, scientists are still learning about the exact mechanisms of how vaccines work and how the antibodies that vaccines prompt the body to create can neutralize a pathogen. The spread of HIV, which is resistant to most antibodies the body produces against it, has made fully understanding this method of action more urgent.

With this in mind, Burton and colleagues sought to tease apart the action of the b12 antibody-one of the rare antibodies that protects against the HIV virus. The antibody, first identified by Burton, Scripps Research Professor Carlos Barbas III, and colleagues in 1992, originally came from the bone marrow of a 31-year-old male who had been HIV positive without symptoms for six years.

In the current study, researchers created mutated versions of b12 to see what effect various changes would have on the antibody�s effectiveness.

�Hopefully, we can work backwards towards a vaccine, using b12 and the very few other really great, broadly neutralizing antibodies against HIV that have been found,� says Scripps Research Senior Research Associate Ann Hessell, who was first author of the Nature paper jointly with Lars Hangartner, a Scripps Research postdoctoral fellow.

Results from the new study suggest the importance of antibody activity against both infected cells and free virus for effective protection. As well as simply binding to HIV, protection was dependent upon the ability of antibodies to interact with immune cell Fc receptors.

Fc receptors are found on the surface of immune cells, such as natural killer cells. The Fc receptor binds to the Fc region of an antibody after an antibody binds to a pathogen, targeting the pathogen for attack by the immune system. Although Fc receptor function was known to be important for the function of antibodies against other diseases, a role in protecting against HIV had never before been demonstrated.

Burton�s team examined the ability of two antibodies mutated from b12, dubbed KA and LALA, to prevent infection using the SHIV/macaque model, in which macaques are challenged with a hybrid human-simian virus that infects the model but is recognized by human antibodies. The KA antibody contained a mutation that prevented it from interacting with the complement cascade, a major component of the immune system responsible for destroying invading pathogens. The LALA antibody contained a mutation that rendered it unable to interact with either the complement pathway or the Fc receptor.

In both mutants, the site where the antibody binds to free-floating virus was unaltered, allowing the researchers specifically to investigate the importance of the complement cascade and Fc receptor system for preventing infection.

�We saw that the KA antibody, which could still bind to the Fc receptors on the immune cells but not to the complement cascade, protected the animals from becoming infected just as the wild type b12 antibody,� says Hessell. �In contrast, the LALA group became infected much like the controls.�

The results provide the first evidence that the Fc receptor, but not the complement cascade, is important to the function of the b12 antibody in preventing HIV infection.

Additional in vitro experiments revealed that the wild type and KA antibodies, but not the LALA antibody, blocked infection more efficiently in the presence of other effector cells of the immune system.

�Our results are fully consistent with the antibody doing two jobs,� says Burton, �job one, stick to the virus; job two, recruit immune cells to come and kill infected cells.�

SIV infection of natural hosts provides new insights into HIV disease complexity

Thu, 06 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Three related papers published in the Sept. 1 edition of The Journal of Immunology provide key new insights into the complexity of HIV/AIDS. Don Sodora, Ph.D., a principal investigator in SBRI�s Viral Vaccines Program who recently joined SBRI from the University of Texas, Southwestern Medical Center, is senior author on one of three papers that collectively show CD4 T-cell depletion, a critical symptom of AIDS, is likely a part of a multifaceted scenario that triggers disease rather than the only cause.

In an HIV-infected person, CD4 T-cells (white blood cells that play a central role in creating immunity) decline and, at a certain point, the person gets sick and dies. This rapid and dramatic loss of CD4 T-cells is considered to be a key determinant of AIDS disease. However, in natural hosts, like the sooty mangabey (an African monkey species), simian immunodeficiency virus (SIV) induced CD4 T-cell depletion can be comparable to that in humans, but the monkeys do not show clinical signs of AIDS. �Our assessment of these natural hosts like mangabeys offers insight into the disease and shows us that progression to AIDS likely results from the cumulative effects of HIV/SIV replication, CD4 T-cell depletion, generalized immune activation and non-CD4 T-cells depletion or dysfunction,� said Sodora.

Sodora�s paper provides evidence, using the sooty mangabey SIV natural host, that virally induced CD4 T-cell depletion, by itself, is not sufficient to induce AIDS in a natural host. �When we first observed the dramatic CD4 depletion in all the tissues we examined in these monkeys, we were concerned that they might begin to exhibit clinical signs of AIDS,� said Jeffrey Milush, Ph.D., lead author on the paper. �But after more than six years, we are sure that CD4 depletion by itself does not necessarily result in progression to AIDS�.

Sodora contributed to a second paper, with senior author Guido Silvestri, M.D., of the University of Pennsylvania. In a study of disease free SIV�infected sooty mangabeys, Silvestri proposes that these African monkeys preserve immune function despite a major loss of mucosal CD4 T-cells as a result of an evolutionary adaptation to reduce immune activation in response to virus replication.

The third of the three papers published this week in The Journal of Immunology, with Ivona Pandrea, M.D., Ph.D., and Cristian Apetrei, M.D., Ph.D., from Tulane University as lead authors, shows that a severe loss of intestinal CD4 T-cells in another natural host, the African green monkey, is also not predictive of SIV virulence.

�These three papers published together indicate that CD4 T-cell depletion is one part of a more complex scenario that results in the clinical signs identified as AIDS,� Sodora said. �We hope that studies in these natural host models will lead to improved HIV vaccines or new therapeutics that might someday make HIV-infected people more like these disease-resistant sooty mangabeys.�

UCLA/RAND study shows that many children of HIV-positive parents are not in their custody

Wed, 05 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new joint study by UCLA and the Rand Corp. shows that more than half of children with an HIV-infected parent are not consistently in that parent�s custody.

Researchers found that during the two-year study period, 42 percent of children were not in the HIV-infected parent�s custody at any time.

The research is the first to use data from a nationally representative sample of people in care for HIV infection to investigate the custody status of children. The findings will be published in the online version of the peer-reviewed journal Pediatrics on Sept 4.

�Children of HIV-infected parents are at risk for behavioral and emotional problems. A stable home may help these children and their parents cope with the effects of HIV on the family,� said lead author Burt Cowgill, M.P.H., a doctoral candidate in the department of health services at the UCLA School of Public Health and a researcher at the UCLA/Rand Center for Adolescent Health Promotion. �By understanding whether children of HIV-infected parents remain in their parent�s custody, pediatricians and other physicians may be able to help families address custody issues and offer referrals to social services.�

Cowgill added that pediatricians may also want to suggest that HIV-infected parents include future custodians in their children�s doctor visits so that these individuals are familiar with the physical and mental health needs of the children.

Using data from the Rand Corp.�s HIV Cost and Services Utilization Study, the team investigated whether HIV-infected parents had maintained custody of their children during the two-year period from 1996 to 1998. They found that 47 percent of children remained in the custody of an HIV-infected parent, while 42 percent were not in the parent�s custody at any time. The remaining 11 percent were out of their parent�s custody at some time during the study period.

HIV-infected fathers, parents with more advanced HIV disease, drug-using parents and parents with at least one hospital stay were less likely to have custody of their children.

A child�s other biological parent or other family members (grandparents, aunts/uncles) were most likely to be the alternate custodian. Parents cited drug use (62 percent) and financial hardship (27 percent) most often as reasons for losing custody of their children. Only 10 percent of HIV-infected parents mentioned the effects of HIV/AIDS as a reason for not maintaining custody of their children.

�Improved treatments for HIV have enabled many HIV-infected parents to live longer. Parents continue to face obstacles that can affect their ability to maintain custody of their children, including financial hardship, ongoing drug use, and the effects of HIV/AIDS and medications used during treatment,� said the study�s primary investigator, Dr. Mark Schuster, professor of pediatrics and public health at the David Geffen School of Medicine at UCLA and director of health promotion and disease prevention at Rand.

Novel HIV vaccine created at The Wistar Institute funded for clinical development

Fri, 31 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (PHILADELPHIA) � A promising new HIV vaccine created at The Wistar Institute has received funding for clinical development aimed at moving the vaccine into human clinical trials as soon as possible.

With $13.3 million in funding over five years, the planned trials will be conducted under the auspices of the Integrated Preclinical/Clinical AIDS Vaccine Development Program of the National Institute of Allergy and Infectious Diseases. The Wistar Institute scientists will collaborate with researchers at Emory University, the University of Pennsylvania, Harvard School of Public Health, MRC/UVRI Uganda Research Unit, and the National Institute for Communicable Diseases in South Africa. The start date for the project is September 1.

�We believe our vaccine, which is built on a novel chimpanzee virus backbone, has unique immunological advantages over other HIV vaccines currently in testing,� says Hildegund C.J. Ertl, M.D., professor and Immunology Program leader at The Wistar Institute. Ertl, principal investigator for the newly funded project, is also director of the Wistar Institute Vaccine Center. �In preclinical studies, the vaccine induced a vigorous immune response in monkeys, and we are hopeful it will do the same in humans.�

Many vaccines currently in development are based on modified human adenoviruses, known as vectors, that incorporate genetic elements from target pathogens to stimulate a protective immune response to those pathogens. These vaccines can work well, but there is an unaddressed problem with this approach, which is that many people receiving the vaccines will have pre-existing immunity to the human viruses upon which they are based, largely negating their effectiveness. About 45 percent of adults in the United States, for example, have pre-existing immunity to a strain of human adenovirus being used as an HIV vaccine vector in current clinical trials.

To circumvent this potential difficulty, the Wistar-led team has developed a series of vaccine vectors based on chimpanzee adenovirus strains, which possess the immunological strengths of human adenoviruses without their drawbacks. The Wistar vaccine will undergo early stage clinical testing for safety and then for its ability to induce an immune response. In the latter trial, the vaccine will be given as a four-part series of inoculations.

Another important aspect of the new HIV vaccine is that it seeks to stimulate a cellular immune response to HIV rather than an antibody response. The cellular immune response corresponds to the T-cell arm of the immune system, while the antibody response corresponds with the B-cell arm of the immune system.

�Based what we know about HIV and the immune system�s response to the virus, it may not be possible to create a vaccine that generates antibodies able to neutralize HIV,� says Ertl. �For this reason, we and others are now focusing our attention on developing a vaccine that stimulates the production of anti-HIV CD8+ T cells, which have been shown to reduce viral load, although they do not prevent infection. Our vaccine has induced unprecedented levels of activated CD8+ T cells in experimental animals, and we are eager to see if it can perform as well in humans.�

Pill box organizers increase HIV patients' adherence and improve viral suppression

Thu, 30 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Inexpensive pill box organizers are an easy, successful, and cost-effective tool to help patients take their medications as prescribed, according to a new study of low-income urban residents living with HIV infection by authors from the Berkeley School of Public Health and the University of California, San Francisco (UCSF). The research is published in the Oct. 1 issue of Clinical Infectious Diseases, now available online.

�Clinicians and pharmacists can meaningfully improve treatment outcomes with simple and inexpensive strategies, such as pill box organizers, to help people organize how they take medication,� said senior author David Bangsberg, MD, MPH, of UCSF.

Incomplete adherence to HIV therapy is the most common cause of incomplete viral suppression, drug resistance, disease progression, and death among people living with HIV/AIDS. The subjects of this study, who were recruited from homeless shelters, free food programs, and single-room occupancy hotels, are thought to be at elevated risk for poor adherence partly because of the high rates of substance abuse, untreated mental illness, and unstable housing.

Patients in this difficult-to-treat population were given inexpensive pill box organizers to use with their antiretroviral medications. Study organizers made a total of 3,170 unannounced visits every three to six weeks to the subjects� places of residence and compared the number of pills remaining in the patients� possession with the number that would be expected to remain if the patients were perfectly compliant with the treatment regimen.

Pill box organizers were associated with a 4 percent improvement in adherence, 0.12 log reduction in HIV viral load, and an estimated 11 percent reduction in the risk of progression to clinical AIDS. At only $5 per pill box, this intervention was highly cost-effective.

�While this population has often been regarded as having difficulty with adherence,� the authors write, �adherence problems are by no means limited to patients with low socioeconomic status.� Lead author Maya Petersen, PhD, from the Berkeley School of Public Health, adds, �Incomplete adherence is a major problem that prevents people from realizing the full benefits of a wide range of treatments for chronic diseases, such as hypertension and diabetes mellitus. Thus, the findings of this study have the potential to inform a wide range of diseases, not just HIV.

�It would be interesting to explore whether changes in packaging or delivery of antiretrovirals and other drugs could be used to reproduce the benefits of pill box organizer use. One model to consider is oral contraceptive therapy, which is routinely dispensed using labeled blister packs, a kind of pre-packaged version of a pill box. Antiretroviral regimens are generally more complicated, but a modification of this general model at either a pharmacy or manufacturer level might be possible, with wide-ranging patient benefits.�

HIV research in sub-Saharan Africa receives major boost from Wellcome Trust

Wed, 29 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The Africa Centre for Health and Population Studies, based in an area of South Africa where over one in five people are HIV infected, is to receive approximately �15 million over five years, subject to a three year review, from the Wellcome Trust, the UK's largest medical research charity. The Centre will use the funding to improve the health status of people in the area, with a particular focus on HIV infection.

Initiated in 1998 in KwaZulu-Natal, the Africa Centre is a research collaboration between the South African Medical Research Council, the University of KwaZulu-Natal and the Wellcome Trust. It carries out a multidisciplinary programme of research reflecting population and health priorities in sub-Saharan Africa, particularly HIV. Recent successes of the Centre include a study showing the importance of exclusive breastfeeding in preventing transmission of HIV from mother to child.

The Wellcome Trust grant will help us in our goal of keeping HIV negative people negative and HIV infected people optimally cared for, says Professor Marie-Louise Newell, Director of the Centre. In South Africa, as in many areas of sub-Saharan Africa, HIV is a major problem, compounded as it is by poverty, migration and lack of access to effective treatments.

With the renewal of funding from the Wellcome Trust, the Africa Centre aims to address questions that will inform the development of appropriate interventions for a community with an HIV prevalence in adults of over 20% and high levels of poverty and unemployment. Researchers at the Centre will monitor the impact of HIV on individuals, their households and the wider community, combining data collected within the bi-annual household survey with that from the annual individual level HIV, health and behaviour surveillance.

In particular, the researchers will look at key questions, such as how communities, households and individuals are affected by simultaneous epidemics of HIV, sexually transmitted infections and tuberculosis; how HIV negative people can be supported to remain uninfected; how best to deliver HIV-related health care in a low-income, resource-poor setting; and how to improve the health of children and adults in an environment challenged by HIV and other adversities. The researchers will extend their HIV research to the over-50s, a vastly under-researched group.

The Africa Centre will also play an important role in monitoring and evaluating the Anti-Retroviral Treatment (ART) Programme, currently being rolled out across Africa, the largest public health programme ever contemplated on the continent. The Centre is one of the few settings where the effects of ART delivery can be monitored and evaluated comprehensively at both population and individual level, through data collected within the population-based HIV and household surveillance linked with the clinical cohort information collected within the HIV-ART programme.

The impact of the HIV/AIDS pandemic on societies is without precedent in recorded human history, and South Africa is particularly severely affected, says Professor Newell. In the last 3 years, there has been an enormous effort to roll-out ART across sub-Saharan Africa. Over the coming 5 years, the Africa Centre will evolve from a research centre focused on description to one focused on intervention and implementation. The detailed knowledge of the population obtained since 2000, in addition to the well-resourced ART programme in the sub-district, uniquely places the Africa Centre to answer our primary research question: what is the long-term impact for the population of a well-functioning and comprehensive ART programme in a resource-poor, rural setting

The research at the Africa Centre is highly relevant for South Africa, but also will impact on the rest of Africa, says Dr Mark Walport, Director of the Wellcome Trust. Professor Newell and colleagues are tackling some of the most important questions in HIV research, particularly those dealing with interventions for preventing HIV transmission and the impact of antiretroviral therapy on HIV incidence.

The support was welcomed by Professor Malegapuru Makgoba, Vice-Chancellor of the University of KwaZulu-Natal in South Africa.

�The research at the Africa Centre, situated in rural northern KwaZulu-Natal is unique, cutting-edge and of profound importance to the understanding and interventions on the HIV/AIDS epidemic locally and globally,� says Professor Makgoba. �The renewed funding from the Wellcome Trust is a welcome boost that serves as an inspiration to the programme itself and the scientists researching at the Centre. The University of KwaZulu-Natal is honoured to be associated with this Centre of excellence.�

The Africa Centre is one of four Wellcome Trust major overseas programmes. Others include programmes in Kenya, looking in particular at malaria and childhood infections, and in Malawi, focusing on health problems of local and regional significance such as malaria, HIV, anaemia, tuberculosis and other bacterial and viral infections.

High-risk behaviors could lead to HIV epidemic in Afghanistan

Tue, 28 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) In a report that is among the first to describe the prevalence of HIV and Hepatitis B and C viruses in Afghanistan, a researcher from the University of California, San Diego (UCSD) School of Medicine voiced concerns that increasing injection drug use and accompanying high-risk behavior could lead to an HIV epidemic in Afghanistan.

�Our findings suggest that interventions to reduce high-risk behaviors among injection drug users are urgently needed in Afghanistan,� said Catherine S. Todd, M.D., MPH, assistant professor in UCSD�s Division of International Health and Cross-cultural Medicine, who is currently working in Kabul, Afghanistan. The findings are published in the September issue of the journal Emerging Infectious Diseases.

Although HIV prevalence is currently low among injection drug users in Kabul, Todd and colleagues with the National HIV/AIDS Control Program of the Afghan Ministry of Public Health found that risky injecting and sexual behaviors were alarmingly high. The incidence of Hepatitis C infection was also high, which could foreshadow an increase in HIV rates.

�It is important to educate the public about this looming problem in Afghanistan,� said Dr. Saifur Rehman, manager of the HIV/AIDS Control Program of the Afghan Ministry of Public Health, who added that one of the biggest obstacles to intervention programs is lack of funding. Afghanistan has received a $10 million grant from the HIV/AIDS programs of the World Bank for three years and has a pending proposal to the Global Fund. Programming for drug users, directed towards reducing or containing adverse health, social, and economic consequences, is a major component of these plans. The country continues to seek other support to help deal with the potential increase in HIV � a problem which, Rehman says, is of unknown proportions. �It is not clear how many cases we have, but there are probably many more than are reflected by available test results,� he said.

The research team conducted a study of 464 injection drug users in Kabul, age 18 and older, which was administered between June 2005 and June 2006. The study was conducted through the Voluntary Counseling and Testing Center at the Central Polyclinic in Kabul, an Afghan Ministry of Public Health facility. Pre- and post-test counseling and rapid antibody testing for HIV and HCV were performed, and all participants received risk reduction counseling, condoms and sterile syringes.

Among this group of Afghan males, high-risk behaviors were common, including sharing syringes (50%), paid sex with a women (76%), and sex with men or boys (28%.) More than half had been incarcerated in prison, 21 percent of them, more than once.

The prevalence of infection with HIV was calculated at about three percent while 38% of the respondents tested positive for Hepatitis C (HCV) infection. HCV was associated with the sharing of needles or syringes, duration of injecting, and having received injections from a non-medical provider. The relatively high prevalence of HCV may potentially foreshadow an HIV epidemic, as these infections share common risk factors.

�The window of opportunity is rapidly closing to avert an HIV epidemic among Afghan injection drug users. The low prevalence of HIV infection is unlikely to continue in the presence of high-risk behavior,� said Todd, adding that the higher prevalence of hepatitis C may be a harbinger of trends with HIV.

Central Asia is experiencing a rapid increase in HIV cases, largely driven by injection drug use. Afghanistan is the largest global producer of opium; recent UNODC reports estimate there are 50,000 heroin users in the country. While opium has been used for centuries in Afghanistan, the researchers� data suggests that injection drug use in Kabul is a relatively new behavior.

A combination of outreach, HIV testing and counseling, access to sterile syringes and drug substitution therapies have been credited with stabilizing HIV rates in other international settings, the study noted. The researchers conclude that a scale-up of needle exchange and other harm-reduction programs, particularly in prisons, is necessary to prevent an HIV epidemic in Afghanistan.

Methamphetamine study suggests increased risk for HIV transmission

Mon, 27 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) WINSTON-SALEM, N.C. � New findings that one in 20 North Carolina men who have sex with men (MSM) reported using crystal methamphetamine during the previous month suggests increased risk for spreading HIV and other sexually transmitted diseases (STD), according to researchers from Wake Forest University School of Medicine and colleagues.

The rate of methamphetamine use among 1,189 MSM was 30 times higher than levels reported in the general U.S. population over the same period. Methampehtamine, or �meth,� is a highly addictive stimulant that has been found to impair judgment, decrease inhibition, increase impulsivity and enhance sexual sensitivity � which can all increase the potential for transmitting HIV.

The study�s authors found that participants who reported using methamphetamines were more likely to report inconsistent condom use during anal sex within the past three months, a history of STD infection, being HIV-positive and using medications designed to treat erectile dysfunction.

�Until now, there has been little data on meth use in the Southeast,� said lead author Scott D. Rhodes, Ph.D. M.P.H., associate professor in the Department of Social Sciences and Health Policy. �Our findings, including that meth users were more likely to be HIV-positive, suggest that prevention, intervention and treatment efforts are urgently needed.�

Rhodes noted that some of the men reported having sex with both men and women, which means the risk of HIV extends to both sexes.

The study�s results will be published on Aug. 20 in AIDS Patient Care and STDs, a leading AIDS journal that provides the latest research for clinicians and researchers. It is among the first to document meth use among MSM in the South, which carries a disproportionate HIV, AIDS, and STD burden, with 46 percent of newly identified cases.

�The findings underscore the need for further research and intervention,� said Rhodes. �The HIV/AIDS epidemic is clearly not over. We must develop innovative intervention approaches designed to reach communities at highest risk. Men who have sex with men, whether or not they identify themselves as gay, who use drugs like methamphetamines are clearly at higher risk. Yet currently nothing is being done in the Southeast.�

Participants were recruited in 2005 in five gay bars and in five geographically defined internet chat rooms in central North Carolina (primarily rural/suburban areas) and were asked to complete a brief assessment of drug use and other risk behaviors. Of the 1,189 MSM, two-thirds self-identified as black or other minorities, and 25 percent as bisexual. The mean age was 29 years.

In addition to being more inclined to risky sexual behaviors, the study participants who said they used methamphetamines were also more likely to report having higher education and health insurance coverage.

�Because users of methamphetamines were more likely to have higher educational levels and report having health insurance, we must change the way we think about meth users and develop sophisticated prevention strategies that are appropriate for these types of users,� noted Rhodes. �In addition, the link between meth use and the use of drugs for sexual dysfunction among a young population deserves attention. Meth use in combination with one of these medications may be having an even more profound impact on the HIV and STD disease epidemics in the South.�

Rhodes is also affiliated with the Maya Angelou Research Center on Minority Health at Wake Forest. In 2006, Rhodes won the New Investigator Award in Clinical Sciences at Wake Forest.

Pitt's School of Medicine gets $16M for HIV structural biology center

Mon, 27 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH, Aug. 27 � The National Institutes of Health (NIH) announced today that it is awarding the University of Pittsburgh School of Medicine a $16 million, five-year grant to establish the Pittsburgh Center for HIV Protein Interactions (PCHPI). Research at the center will give scientists detailed new insights into the life of HIV, the virus that causes AIDS, and have important implications for developing new drug targets.

One of three centers being funded jointly by the National Institute of General Medical Sciences (NIGMS) and the National Institute of Allergy and Infectious Diseases (NIAID), the PCHPI will specialize in developing methods and tools for understanding what happens to the HIV virus, both structurally and at an atomic level, immediately after it enters the cell and prior to becoming integrated into the host genome. By doing this, PCHPI researchers will be able to identify which cellular processes and components are hijacked by HIV for its nefarious purposes.

�We know how HIV attaches to its host and how it gains entry to cells, but what happens between when it first enters into the cells and when it integrates itself into the host genome is still a mystery. By elucidating the important events during this period, we believe we�ll learn a great deal about the how the virus can be stopped,� said PCHPI director, Angela Gronenborn, Ph.D., the University of Pittsburgh Medical Center Rosalind Franklin Professor and chair of the department of structural biology, University of Pittsburgh School of Medicine. Dr. Gronenborn, who recently was elected to the National Academy of Sciences, is one of the country�s leading structural biologists and an internationally renowned specialist in the application of nuclear magnetic resonance (NMR) spectroscopy for investigating the biochemical mechanisms and cellular structures involved in HIV pathogenesis. The other two NIH-funded HIV structural biology centers are led by Alan Frankel, Ph.D., a biochemist at the University of California, San Francisco, and Wesley Sundquist, Ph.D., a biochemist at the University of Utah.

Although researchers have determined the structures of many HIV proteins in isolation, they know the structures of only a few HIV proteins in their functional state, that is, when they interact with cellular components of host cells. Because HIV works through such interactions, knowing their structures will provide targets for new generations of anti-AIDS drugs. Center researchers will use NMR and X-ray crystallography to identify and characterize atomic structures of key virus interactions and other pivotal events in the immediate post-entry stage of the viral life cycle. They also will use advanced imaging technologies such as cryo-electron tomography to better study the structure of HIV and the host cellular components with which it interacts.

As part of its mission to collaborate with researchers nationally and globally, the center will make the methods and tools it develops available to the HIV research community at large. These resources are expected to have major impact in the global fight against AIDS, which is estimated to afflict more than 40 million people worldwide.

�HIV is so challenging to treat because the virus is extremely adept at evolving resistance against therapies that target individual HIV proteins. Efforts by Dr. Gronenborn and her colleagues to identify and image pivotal virus-host cell interactions could forge new avenues for drug discovery,� explained Ravi Basavappa, Ph.D., the NIGMS program director for the new centers.

In addition to studying the structure and interactions of HIV using advanced technologies, another focus of the center will be to engage virologists, cell biologists and structural biologists in a collaborative effort toward deciding which of these interactions make the best drug targets.

�For many years, structural biologists and virologists have not worked closely in the area of HIV-targeted drugs. This center will allow the two to work collaboratively and help them to determine fairly quickly whether their hypotheses about what happens at the molecular and atomic levels of HIV infection are accurate,� said Dr. Gronenborn.

IAVI, CDC and USMHRP release new data redefining laboratory reference ranges in Africa

Tue, 21 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (SEATTLE, August 21, 2007) Leading researchers from the International AIDS Vaccine Initiative (IAVI), the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Military HIV Research Program (USMHRP) presented final results today from a collection of independent studies reexamining the medical criteria for including African volunteers in AIDS vaccine trials. The findings, presented at the AIDS Vaccine 2007 Conference in Seattle, suggest that many healthy Southern and East Africans have, in the past, been excluded from participating in trials based on laboratory reference ranges that were developed for Western populations and may not be appropriate locally. Implementation of the results of the studies should improve participation of African volunteers in clinical trials for new drugs and vaccines against emerging infectious diseases currently ravaging Africa, including AIDS, TB and malaria, and enable clinicians to better monitor and define adverse events in trials.

In the first reference range studies conducted on such a large scale, researchers from the involved organizations examined the blood tests of approximately 5,500 clinically healthy HIV-negative volunteers across a dozen clinical sites in four African countries. For some markers, the studies revealed differences between the norms usually found in healthy Africans and the reference values developed for populations in North America and Europe.

These studies are important for a range of research on neglected diseases, from HIV vaccines to malaria and TB drug therapy, said Anatoli Kamali, an epidemiologist with the Medical Research Council/Uganda Virus Research Institute and the Protocol Chair of the IAVI-sponsored study. For the first time, African volunteers seeking to participate in trials will now be evaluated according to blood reference ranges that accurately reflect their populations. Furthermore, we will now be able to interpret laboratory abnormalities detected during vaccine or drug clinical trials more accurately in Africa.

We are excited about these findings. Localized reference parameters could significantly help us to improve recruitment for clinical trials in less-industrialized nations, as well as better evaluate the health of our volunteers throughout the course of these studies, said Mark de Souza, Director, International Laboratory Program, USMHRP. In one of its trials in Uganda, the USMHRP screened out 58% of potential participants because of lab abnormalities using Western ranges. In a second trial, the screen-out rate decreased to 23% using a norm localized for the trial site. In addition, says de Souza, With local ranges, we can better detect reactions to candidates, enlist a more typical cohort in the trial and thus test it on the most representative group of volunteers, possibly significantly accelerating the search for HIV vaccines for those countries hardest hit by the epidemic.

As part of their two-year study, IAVI and its partners examined blood chemistry and hematology parameters, as well as evaluated kidney and liver functions and the immunological health of thousands of volunteers. Individuals with clinical symptoms or abnormal physical exams and anyone infected with HIV, hepatitis B or C, or untreated syphilis were excluded from the study. These studies should be valuable to anyone designing trials of preventive medicines or vaccines for these parts of Africa, concluded Pat Fast, Executive Director of Medical Affairs, IAVI. Improving participation in AIDS vaccine trials among populations in desperate need of new AIDS technologies is the first step in ultimately reaching our goal of ending the AIDS crisis.

Currently, Africa remains the epicenter of the AIDS pandemic with 2.8 million new infections annually. In 2006 alone, almost two-thirds (63%) of all persons infected with HIV were living in sub-Saharan Africa. IAVI and partners, as well as CDC and the USMHRP, and other international organizations plan larger-scale trials of promising vaccine candidates over the coming years in the Eastern and Southern region of Africa and elsewhere.

AIDS not the downfall of African families; MU study finds poverty is the prevailing issue

Mon, 20 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBIA, Mo. � The media�s message is clear: the AIDS epidemic will be the downfall of families in Africa. A new study by a University of Missouri-Columbia researcher calls that an overstatement. Her study shows that AIDS compounds the issue of poverty in households where poverty is already a prevailing issue, especially when a household loses its primary income earner to AIDS.

�We saw some households that had experienced an AIDS death functioning better than some households that had not experienced an AIDS death,� said Enid Schatz, assistant professor of occupational therapy and director of social science research in the MU School of Health Professions. �We were surprised to see that all the alarmist predictions in the popular media that AIDS will bring an imminent downfall to the African society just did not seem to be true. In fact, because of all the poverty issues, AIDS just seems to be viewed as �just another crisis� to the families in South Africa.�

Schatz spent time with older women in multi-generational households in a rural part of northeast South Africa. The older generation�s government pensions (one of few developing countries to offer this type of assistance) play a crucial role in day-to-day survival in this area where AIDS morbidity and mortality have profound effects on household resources. The study says the elderly are much more likely to be affected, rather than infected, with HIV/AIDS.

�Some of the older women did express that their situations seemed difficult and they expected to be spending these years of their lives resting. However, most often we heard that they feel it is their obligation and responsibility to carry the household financially with their pensions and despite the hardships, most are able to cope,� Schatz said.

Often, the offspring of the elderly in families either die of AIDS or have to migrate to find work because of the high unemployment rate in the rural areas. The households are then left to cope with the loss of income and support previously provided by those who become sick or die of AIDS. If parents migrate to find work, grandmothers must use their pensions, intended to sustain one elderly individual, to maintain an entire household and often even donate to other households. One elderly woman in the study and her husband support 12 people, including seven grandchildren, four of whom are AIDS orphans.

�In the Western perspective we often see households as being unconnected and that is not the case in South Africa,� Schatz said. �We saw families who were very resilient and really taking care of each other. In some cases, grandmothers were caring for their own grandchildren as well as orphans and caring for those sick and dying of AIDS.�

Tumors use enzyme to recruit regulatory T-cells and suppress immune response

Thu, 16 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One way tumors fly under the radar of the immune system is by using IDO, an enzyme used by fetuses to help avoid rejection, to recruit powerful regulatory T cells that turn down the immune response, researchers say.

It was known tumors assemble a protective barrier of regulatory T cells, or Tregs, but how they are such able recruiters was an unknown, says Dr. David Munn, pediatric hematologist/oncologist at the Medical College of Georgia Cancer Center.

People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body, Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue.

Research published online Aug. 16 in The Journal of Clinical Investigation shows IDO, which seems to play a powerful role in tumor survival despite the relatively few number of cells in the tumors draining lymph nodes, directly activates existing Tregs which become strongly suppressive within a day. The number doesnt change a lot, but their activation state changes hugely, says Dr. Munn, corresponding author.

Studies in a tumor animal model show this rapid conversion occurs only in lymph nodes connected to tumors.

The findings further define a tumors survival strategy of first recruiting IDO, which helps recruit Tregs. Tregs then up-regulate the PD-L1/PD-L2 pathway, which has been shown to play an important role in the immune suppression caused by AIDS.

For the first time it creates a link between IDO, regulatory T cells and this novel pathway we dont know much about, says Dr. Munn. Interestingly its a link that appears to come full circle because, as researchers at the University of Perugia in Italy showed in 2003, in the test tube at least, Tregs also help recruit more IDO.

IDO appears to be a sort of linchpin; its a crossroads where a number of mechanisms, some of which are more powerful than IDO itself, come together, says Dr. Munn. Tregs, for example, are much more powerful than IDO. If you take a mouse and remove IDO, it compensates just fine. If you remove Tregs, the mouse dies. But if the tumor uses IDO to recruit and activate Tregs, that is a leverage point.

Therapies aimed at these new leverage points will be most effective when packaged with other emerging and existing treatments, he says.

The FDA has approved early clinical trials of the IDO inhibitor, 1MT, in coming months. A team, led by longtime collaborator Dr. Scott Antonia, hematologist/oncologist and co-leader of the Immunology Program at the H. Lee Moffitt Cancer Center and Research Institute, will begin phase 1 trials of 1MT in patients with lung and other tumors shortly. MCG is pursuing FDA approval to begin trials of the combination of 1MT and chemotherapy in breast cancer patients. Dr. Munn notes that while the IDO inhibitor seems to be a safe drug that doesnt cause autoimmune disorders in mice, it wont be used in patients with autoimmune disorders because it could worsen the disorders.

By combining IDO with chemotherapy, researchers hope to wipe the slate clean of the tumors manipulation of the immune response, says Dr. Munn. We have found that once the tumor gets a hold of the immune system, just giving an IDO inhibitor does not restore everything to normal. The tumor has too much influence on the immune system at that point.

Standard doses of chemotherapy reduce immune system function, creating a window where IDO likely can be more effective. That window may work for cancer vaccines too, which are still under study and getting mixed reviews. Recent reports indicate vaccines can actually increase the number of Tregs in mice with tumors, a problem when fighting cancer but a possible opportunity in which an IDO inhibitor might improve efficacy, Dr. Munn says. An antibody to the PD-L1/PD-L2 already under study in cancer may be another component of a total anti-tumor package.

We have data from a mouse model that while 1MT works modestly by itself, it works significantly better when combined with chemotherapy, says Dr. Munn. I think immunotherapy needs to learn from the finding with multi-agent chemotherapy, which is you need to orchestrate more than one approach. If you give one drug over and over again, the tumor invariably figures out a way to escape, so you always have to combine different strategies. Multiple approaches also reduce the chance of needing toxic levels of any of them.

Early clinical trials of the IDO inhibitor ideally will benefit patients for whom more standard therapies have failed and enable scientists to verify laboratory findings in people, Dr. Munn says. Scientists will carefully monitor Tregs to see if they show evidence of being activated by IDO now that they know what that looks like and de-activated by the IDO inhibitor. Theyll also have to see if Tregs circulating in the bloodstream are good indicators of whats happening or whether tumor biopsies will be needed.

IDO inhibitors potential against tumors as well persistent viruses such as HIV arose out of work MCG scientists, led by Dr. Munn and his long-time collaborator Dr. Andrew L. Mellor, director of the MCG Immunotherapy Center and Georgia Research Alliance Eminent Scholar in Immunogenetics. Their work published in Science in 1998 showed fetuses use IDO indoleamine 2,3-dioxygenase to locally disable a pregnant womans immune system and avoid rejection. They showed then that one way IDO suppresses the immune response is by degrading tryptophan, a natural amino acid important to T cells.

Later, they found that tumors and certain viruses such as HIV also appear to use IDO for protection from the immune response. However, the fact that IDO-expressing cells make up less than 1 percent of the cells in a tumor or its draining lymph node led MCG researchers to look for a population of powerful allies within the immune system that could explain the suppressive impact. Tregs seemed like a good choice. The 2003 paper by Italian scientists, followed by a 2006 paper that showed naïve T-cells exposed to IDO differentiated into Tregs, helped cement that some sort of relationship existed, prompting MCG researchers to further explore the relationship in a tumor animal model.

Its only been in the last year or two that people have begun to realize Tregs spend most of their time in a sort of resting state where they have the potential to be suppressive but are not at that moment, says Dr. Munn. That would make sense, because you dont want your immune system always shut off.

AIDS interferes with stem cells in the brain

Wed, 15 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (La Jolla, CA August 15, 2007) A prominent problem in AIDS is a form of dementia that robs ones ability to concentrate and perform normal movements. Scientists at the Burnham Institute for Medical Research (Burnham) have discovered how HIV/AIDS disrupts the normal replication of stem cells in the adult brain, preventing new nerve cells from forming. Drs. Stuart Lipton, Marcus Kaul, Shu-ichi Okamoto and their colleagues uncovered a novel molecular mechanism that inhibits stem cell proliferation and that could possibly be triggered in other neurodegenerative diseases as well. These findings were made available to medical researchers today through priority publication online by the journal Cell Stem Cell.

A normally functioning adult human brain has the ability to partially replenish or repair itself through neurogenesis, the proliferation and development of adult neural progenitor/stem cells (aNPCs) into new nerve cells. Neurogenesis can take place only within specific regions of the brain, such as the dentate gyrus of the hippocampus.

The hippocampus is the brains central processing unit, critical to learning and memory. aNPCs differentiate, adapt, and assimilate into existing neural circuits and mature with guidance from neurotransmitters, the chemical substances that nerve cells use to communicate with one another. The brains self-renewal through neurogenesis is impaired in AIDS dementia, Alzheimers, Huntingtons, and other neurodegenerative diseases, as evidenced by a greatly reduced number of aNPCs in brain tissue from individuals suffering from these diseases. The Burnham team focused on the determining the effect of a protein associated with AIDS, called HIV/gp120, which plays a key role in the pathogenesis of AIDS dementia.

In initial work with cell cultures in Petri dishes, the researchers methodically ruled out the possibility that HIV/gp120 would be inducing the death of stem cells and determined instead that HIV/gp120 was acting by inhibiting stem cell proliferation. Next, they confirmed these results in a special mouse strain bred to express HIV/gp120 in its brain. This mouse model for AIDS dementia mimics several features of the disease process found in humans. They observed a significant decrease in the number of proliferating stem cells in the brains of HIV/gp120-mice compared with similar tissue from normal, wild-type mice.

HIV/gp120 is known to interact with two receptors, called chemokine receptors, which are expressed on aNPCs. The researchers discovered that the same two receptors were targeted by HIV/gp120 sourced from either mouse or human brain tissue.

In search of a mechanism behind the finding that HIV/gp120 reduced proliferation of aNPCs, the scientists studied the effect of the protein on the cell cycle. Cells undergo seasons or cycles, known as G1, S, G2, and M (for mitosis, or cell division). They found that cells exposed to HIV/gp120 got stuck in the G1 or resting phase, and that the cell cycle was arrested.

Cell cycle is studied intensively by cancer researchers who have delineated certain checkpoint pathways that can jam cell proliferation, one of the key behaviors of cancer. Checkpoint pathways are overcome by cancers when they fool the bodys normal machinery into producing more cancerous cells. With dementia, it turns out that the opposite is true: the Burnham team discovered that HIV/AIDS could co-opt the checkpoint pathway to prevent stem cells in the brain from dividing and multiplying.

One such checkpoint pathway is modulated by an enzyme called p38 mitogen-activated protein kinase (MAPK), whose activity is known to disrupt the cell cycle. In mature nerve cells, the Burnham team had previously shown that HIV/gp120 activates the p38 MAPK pathway to contribute to cell death. Lipton and colleagues now report that the p38 MAPK pathway is also the mechanism underlying decreased stem cell proliferation in the brain associated with HIV/AIDS. Under experimental conditions, they were able to neutralize the p38 MAPK pathway and restore stem cell proliferation.

We show for the first time how HIV/AIDS inhibits proliferation of neural stem cells and prevents the formation of new nerve cells in the adult brain, said Dr. Stuart Lipton, Director of Burnhams Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research.

The fact that the mechanism of action involves the p38 MAPK enzyme is fortuitous because drugs to combat that pathway are being tested for other diseases. If they prove effective, they might also work to protect the brain. Thus, this study offers real hope for combating the bad effects of HIV/AIDS on stem cells in the brain. Lipton went on to state, It will be important to see if HIV/AIDS acts similarly on stem cells for other organs in the human body, as this may impact on the disease process as a whole.

HIV is a 'double hit' to the brain

Wed, 15 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) New evidence reported in the August issue of Cell Stem Cell, a publication of Cell Press, offers a novel perspective on how the HIV/AIDS virus leads to learning and memory deficits, a condition known as HIV-associated dementia. A protein found on the surface of the virus not only kills some mature brain cells, as earlier studies had shown, but it also prevents the birth of new brain cells by crippling adult neural progenitors, the new study finds. Those progenitor cells are the closest thing to stem cells that have been found in the adult brain.

By elucidating the mechanism responsible for the neurodegeneration and dementia seen in people infected with HIV, the findings made in mice that produce the damaging HIV protein may open the door to new therapies, according to the researchers.

The breakthrough here is that the AIDS virus prevents stem cells in the brain from dividing; it hangs them up, said Stuart Lipton of the Burnham Institute for Medical Research and the University of California at San Diego. Its the first time that the virus has ever been shown to affect stem cells.

Its a double hit to the brain, added collaborator Marcus Kaul, who is also of the Burnham Institute and UCSD. The HIV protein both causes brain injury and prevents its repair.

Physicians first recognized that HIV infection could lead to a profound form of dementiamost commonly in those with an advanced stage of the diseaseearly on. The success of antiretroviral therapies in keeping the viral load down has helped to reduce the severity of the dementia in recent years. Nonetheless, the prevalence is rising as HIV-infected people are living longer. The anti-HIV drugs dont infiltrate the brain well, allowing for a secret reservoir of virus, Lipton explained. Such persistent exposure of the central nervous system to HIV is a major risk factor for the development of HIV-associated dementia.

Liptons team previously discovered that the brain deficits could be triggered by gp120the viral coat protein that latches onto human cellseven in the absence of any viral infection. They also showed that the protein disrupts a key cell-cycle pathway (including p38 mitogen-activated protein kinase or MAPK), leading to the death of certain mature neurons.

The researchers now find that gp120 in mice also slows the production of new neurons in the hippocampus, a brain region central to learning and memory. Newborn neurons become integrated into existing brain circuits and are thought to contribute to certain forms of learning and memory, they said.

Moreover, they found that it is the same MAPK pathway earlier linked to the death of mature neurons that lies at the root of the progenitor cells dysfunction. That a similar enzyme is involved in both brain-damaging effects is simply serendipitous, according to the researchers.

Knowing the mechanism, we can start to approach this therapeutically, Lipton said. This indicates that we might eventually treat this form of dementia by either ramping up brain repair or protecting the repair mechanism, Kaul added.

Features of replication suggest viruses have common themes, vulnerabilities

Mon, 13 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) MADISON - A study of the reproductive apparatus of a model virus is bolstering the idea that broad classes of viruses - including those that cause important human diseases such as AIDS, SARS and hepatitis C - have features in common that could eventually make them vulnerable to broad-spectrum antiviral agents.

In a study published today (Aug. 14) in the online, open-access journal Public Library of Science Biology, a team of researchers from the Howard Hughes Medical Institute (HHMI) at the University of Wisconsin-Madison describes in fine detail how an RNA virus known as flock house virus co-opts a cell's membranes to create an intracellular lair where it can safely replicate its genes.

The results provide strong evidence that at least some of the machinery four of the seven distinct classes of known viruses use to reproduce have common attributes. Such a discovery is important because it reveals a common viral theme that may be vulnerable to disruption and could lead to the development of drugs to treat many different kinds of viral infections, much like antibiotics are used to attack different kinds of bacterial pathogens.

It turns out that viruses previously thought of as distinct share common features, says Paul Ahlquist, an HHMI investigator and virologist at UW-Madison. We've found some features of replication that appear to cross over among many viruses.

Using powerful electron microscopy techniques, Ahlquist's group and their collaborators made the first three-dimensional maps of a viral replication complex using flock house virus, which, like all viruses, requires a host cell to make new genetic material and maintain the chain of infection.

In the case of flock house virus, the Wisconsin group found, the virus co-opts intracellular membranes of mitochondria, critical energy-regulating structures found in most eukaryotic cells.

Squeezing into the space between the inner and outer membrane of the double-lined mitochondria, the virus creates tens of thousands of protein-lined, balloon-like pockets where it can make new copies of the viral genome while safe from surveillance and defense mechanisms of the host.

The virus has developed a very elegant strategy, says Ahlquist. It creates for itself a new compartment for RNA synthesis, where it can collect its (constituent) components, organize successive steps of replication, and sequester these steps from other processes in the cell, most importantly, host defense responses.

In essence, the virus is reorganizing the cell to make a new intracellular architecture for its own purposes, according to Ahlquist. The virus is reorganizing the cell to make a new organelle. It is a way to keep out competing processes and alarm-ringers and have a place where it can carry out its processes efficiently and for long periods of time.

The balloon-like sacs or spherules observed by Ahlquist and his colleagues all had narrow necks that transcended the membrane of the organelle to the cytoplasm, the medium inside the cell and in which the organelle is suspended. The neck is a gateway that appears to permit substrates needed for replication to enter and newly made viral genomes to exit.

The virus begins to co-opt the cell as a critical viral protein and viral RNA localize to the budding organelles, Ahlquist explains. The virus takes over most of the available membrane. The protein creates a shell inside the spherule to provide stability, and it is this use of a protein shell in replicating viral genes, the Wisconsin virologist suggests, that could be one of several common themes among different groups of viruses.

Multiple features in the structure and function of these replication compartments appear similar across several virus classes, says Ahlquist. This includes ways in which cell membranes are used to organize virus replication.

The shared features extend to most RNA viruses and a group known as reverse transcribing viruses, which include retroviruses such as HIV, suggesting a possible evolutionary link from a common ancestor.

Even older women at high risk have little interest in being tested for HIV, study finds

Tue, 07 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH, Aug. 7 Few older women were interested in being tested for the virus that causes AIDS despite having significant risk factors for lifetime exposure, according to a study published in the July/August edition of the Journal of Womens Health. The risk is especially great among African-American women, who represent 73 percent of new HIV cases in women over age 50.

Older people largely have been overlooked in HIV prevention and testing programs, and consistently have lower HIV testing rates as compared with younger adults, said Aletha Akers, M.D., M.P.H., assistant professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine and the studys lead author. Those who are tested tend to do so late in their disease, when they are more likely to have overt symptoms such as opportunistic infections. Often, they progress more rapidly to AIDS and die within a year of HIV diagnosis, which leaves little opportunity for treatment or secondary prevention for their partners.

For this investigation, Dr. Akers and her colleagues analyzed data collected from 514 women ranging in age from 50 to 95. The women visited a general internal medicine clinic at a large, inner-city hospital in Atlanta over a period of 11 months in 2001 and 2002. To evaluate attitudes concerning lifetime HIV infection risk and interest in HIV testing, trained research assistants administered a 68-item questionnaire in a private room over the course of a single, face-to-face interview with study participants, most of whom said they were not currently sexually active.

More than 60 percent of the participants had never been tested for HIV, although more than half of them could be described as moderate- to high-risk for lifetime exposure to the virus based on sexual history and other factors. Only 115, or 22 percent of participants, said they would be interested in HIV testing. Their most often cited reasons were curiosity and concern about a current or past sexual partners behaviors. About a third of women had already been tested. Previously tested women were more likely to be younger, sexually active, better educated about HIV and tested at the suggestion of a health care provider.

Most women, however, felt little need for testing. Those who lacked interest were more likely to be older, African-American and not sexually active, said Dr. Akers, who also is an assistant investigator at the university-affiliated Magee-Womens Research Institute. These women had a low perceived risk, which was not always accurate based on their histories. A third of all the women who were not interested in HIV testing reported lifetime risk factors for the disease, but we found that they tended to point to those people when talking about the danger of HIV rather than at themselves or their partners.

In short, women with little HIV knowledge and low perceived personal risk were less interested in HIV testing, a finding that is consistent with attitudes in much younger, high-risk adults, the study found. Fewer than 25 percent of the participants could recall ever receiving counsel to get a test for HIV from a provider, despite their risk factors.

Yet, in part because of a lack of education and prevention efforts targeted at older populations, older women appear to be less capable of accurately assessing their lifetime risk of HIV even when they have significant risk factors and live in communities with high rates of infection, Dr. Akers said. We need to design prevention strategies and AIDS education for this vulnerable population and help providers to incorporate HIV risk screening into the services offered to older women from high-prevalence communities.

UCLA scientists produce functioning neurons from human embryonic stem cells

Tue, 07 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists with the Institute of Stem Cell Biology and Medicine at UCLA were able to produce from human embryonic stem cells a highly pure, large quantity of functioning neurons that will allow them to create models of and study diseases such as Alzheimers, Parkinsons, prefrontal dementia and schizophrenia.

Researchers previously had been able to produce neurons - the impulse-conducting cells in the brain and spinal cord - from human embryonic stem cells. However, the percentage of neurons in the cell culture was not high and the neurons were difficult to isolate from the other cells.

UCLAs Yi Sun, an associate professor of psychiatry and biobehavioral sciences, and Howard Hughes Medical Institute investigator Thomas Südhof at the University of Texas Southwestern Medical Center were able to produce 70 to 80 percent of neurons in cell culture. Sun and Südhof also were able to isolate the neurons and determine that they had a functional synaptic network, which the neurons use to communicate. Because they were functional, the neurons can be used to create a variety of human neurological disease models.

The study results are published today in an early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.

Previously, the system to grow and isolate neurons was very messy and it was unknown whether those neurons were functioning, Sun said. Were excited because we have been able to purify so many more neurons out of the cell culture and they were, surprisingly, healthy enough to form synapses. These cells will be excellent for doing gene expression studies and biochemical and protein analyses.

Suns method prodded human embryonic stem cells to differentiate into neural stem cells, the cells that give rise to neurons. When the time was right, Suns team added protein growth factors into the cell culture that stopped the neural stem cells from self-renewing and prodded them into differentiating into neurons. To isolate the cells, Sun and her team added an enzyme that digests a sort of protein matrix that holds cells in culture together. The neurons could then be separated from the neural stem cells that had not yet differentiated, a sort of chemical round-up that isolated the neurons. The cells were then put into a cell strainer that allowed passage through of the isolated neurons.

The large number of pure neurons produced will allow Sun and her team to study their biological form and structure, the genes they express, the development of synapses and the electric and chemical communication activities within the synapse network.

We will be able to study the cellular properties of neurons in a very defined way that will maybe tell us what goes wrong in diseases such as Alzheimers and Parkinsons, Sun said. Were currently creating many models of human neurological diseases that may provide the answers were looking for. We dont know what causes prefrontal dementia, Huntingtons disease or schizophrenia. The key is likely in the quality of neuronal communications. By studying the chemical and electrical transmissions, we may be able to determine what goes wrong that leads to these debilitating diseases and find a way to stop or treat it.

Sun will be among the first researchers to be able to study true neuron function.

A second important discovery in Suns study showed that two embryonic stem cells lines derived in similar manners, and therefore expected to behave similarly when differentiating, did not. Using the same techniques to prod the two embryonic stem cells lines to differentiate, Sun found that one line had a bias to become neurons that are found in the forebrain. The other line differentiated into neurons found in rear portions of the brain and spinal cord. The finding was surprising, and significant, Sun said.

The realization that not all human embryonic stem cell lines are born equal is critical, Sun said. If youre studying a disease found in a certain part of the brain, you should use a human embryonic stem cell line that produces the neurons from that region of the brain to get the most accurate results from your study. Huntingtons disease, for example, is a forebrain disease, so the neurons should be differentiated from a cell line that is biased to produce neurons from the forebrain.

Sun said there are ways to prod an embryonic stem cell line biased to become neurons found in the rear brain to become neurons found in the forebrain. However, there are limits to how much prodding can be done.

Sun and her team confirmed that the two embryonic stem cell lines were different through gene expression analysis neurons that perform different functions in different parts of the brain express different genes. The cell line prone to becoming neurons found in the forebrain expressed genes typically found those neurons, while the other line expressed genes found in the rear brain and spinal cord.

Sun and her team now are studying why the two human embryonic stem cell lines have biases to become different types of neurons.

If we knew that, we might be able to tweak or alter whatever is driving the bias so that limitation in the stem cell line could be bypassed, Sun said.

NYUCD's Dr. Daniel Malamud awarded $6.8 million NIH grant for HIV research

Thu, 02 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) New York University College of Dentistrys (NYUCD) Dr. Daniel Malamud, a professor of basic science and craniofacial biology, has been awarded a five-year, $6,800,000 grant from the National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH) to head up a research collective consisting of four interrelated research projects, along with Administrative/Biostatistical and Clinical Core components. The collectives overall goal is to define the interactions between host defense molecules and bacteria in HIV infection and subsequent antiretroviral therapy.

The collective consists of teams from NYUCD, New York University School of Medicine (NYUSoM) and the Aaron Diamond AIDS Research Center (ADARC). Dr. Malamud has assembled a talented group of investigators--all located within a few blocks of each other on First Avenue in New York City.

The study is an intriguing one, notes Dr. Malamud. We are going to recruit a population of people that are HIV-infected but are drug naïve, so they havent even been put on treatment yet. New York City is probably one of the few places in the country where the study could be done.

The entire proposal utilizes the same case-controlled study population consisting of 85 HIV+, HARRThighly aggressive anti-retroviral therapy-naïve subjects who will subsequently begin antiretroviral therapy. There will also be a similar cohort of HIV- subjects. The clinical core will obtain oral and GI samples, monitor patient progress, carry out complete oral health examinations, and maintain all subject records.

Were going to take a variety of samples from the subjects, and then we are going to put the HIV+ subjects on drug treatment for two to three years, said Dr. Malamud. We want to see how various parameters throughout the GI tract are affected by HIV infection and then by the subsequent control of HIV through a cocktail of drugs, known as HARRT.

The first of the research collectives four projects, Project 1, headed by Dr. Linqi Zhang, of the ADARC, will determine the whole saliva proteome comparing HIV-, HIV+/HAART naïve, and HIV+ post-HAART samples. Dr. Zangs studies will focus on soluble molecules that are part of the host innate defense system.

Dr. Malamud is a well recognized HIV expert in the dental science field, said Dr. Zhang. When I learned that Dr. Malamud was coming to NYU, I had the opportunity to show him my lab at ADARC where we have been very interested in HIV infection in mucosal settings, in particular the oral cavity and the GI tract. With this study, we will be able to compare bacterial and viral factors in these two distinct environments--in the same host--so we can better understand the disease and help to design better anti-HIV drugs and vaccines.

Project 2, headed by Dr Yihong Li, associate professor of basic science and craniofacial biology at NYUCD, will define the oral microbiota in HIV- ¬vs. HIV+ saliva samples, and HIV+ before and after HAART. Dr.Lis studies will focus on overall microbial diversity, and quantitation of bacteria that are altered after HIV infection, and/or related to caries and periodontal disease.

We will collect samples from multiple sites from the same individual, said Dr. Li, which will enable us simultaneously to compare the bacteriological composition, in order to make inferences about shifts in the ecological balance of the microbial community. To date, no such study has been done or reported in the literature.

Project 3, headed by Dr. Michael Poles, NYUSoM, will study the remainder of the GI track using endoscopy to obtain fluid and biopsy samples. Dr. Poles study will focus on innate immune mediators and GI microbes, and his data compared to Projects 1 and 2.

This collaboration dovetails beautifully with my research interests, said Dr. Poles. I am most excited to be working with such an amazing PI as Dr. Malamud and the amazing cadre of investigators he has assembled. I expect that this project will yield an enormous amount of vital information about HIV pathogenesis and mucosal immunology.

Project 4, headed by Dr. Malamud, will study antibacterial and antiviral activities in saliva, focusing on the innate host defense system. In addition, Dr. Malamud will determine the ability to infect buccal vs. rectal tissue in vitro, and compare the HIV-1 variants obtained from oral, GI, and blood. The Administrative/Biostatistical Core, lead by Drs. Malamud and Norman, will oversee the entire study via an Executive Committee and an External Advisory Committee. All data and statistical analyses will be handled by this core.

Medical residents score poorly in diagnosing and managing tuberculosis

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) When quizzed about their knowledge in diagnosing tuberculosis and deciding on the best treatment, medical residents in Baltimore and Philadelphia get almost half the answers wrong, according to a survey by TB disease experts at Johns Hopkins and elsewhere.

In the survey, published online Aug. 2 in the British journal BMC Infectious Diseases, 131 medical residents were asked to answer 20 basic questions about the contagious lung disease, recently made the subject of international concern when a traveler was believed to have its most severe form.

According to researchers, the overall median test score for the training physicians, with one-half scoring higher and the other half scoring lower, was just 55 percent.

Results showed that the recent medical school graduates got three-fifths of the answers wrong (with a median score of 40 percent) for recognizing and treating latent TB, the most common form of the infection. In latent TB, a person is infected with the tubercle bacterium but lacks symptoms and is not contagious, yet is still at risk for developing active disease later on.

Just over half of the questions about diagnosing active TB, when an infected person develops TB-related symptoms and is more likely to infect others, were answered correctly (with a median score of 57 percent). Symptoms of active TB include fever, cough, night sweats and weight loss.

According to the U.S. Centers for Disease Control and Prevention, an estimated 10 million to 15 million Americans have latent TB and are at risk of developing active disease.

On two-thirds of the questions about the toxicity of current drug regimens and about the link between TB and HIV infection, physicians gave the right answer (with a median score of 63 percent for both questions.)

Despite the poor results for trainees, people cannot assume that lack of comprehensive knowledge about tuberculosis leads to poor patient care, says lead study author Petros Karakousis, M.D. Medical residents may be quick to consult experts in infection control, infectious diseases, or in pulmonary medicine to assist in diagnosis, isolation and treatment.

According to Karakousis, an assistant professor at The Johns Hopkins University School of Medicine and its Tuberculosis Research Center, Our results demonstrate that improved training is needed about how best to diagnose and care for people with latent and active TB because physicians training at urban medical centers are most likely to be the first point of contact for people with previously undiagnosed TB.

Karakousis says large metropolitan areas are prone to more cases of TB because of social factors, including high rates of homelessness, drug use, incarceration and immigration, as well as HIV infection.

He points out that the survey results were not all bad, with most medical residents understanding the main facts about how Mycobacterium tuberculosis is transmitted (with a median score of 95 percent).

Most people with active TB develop symptoms over weeks, so what is needed is more training in the outpatient setting and in the community in addition to the hospital wards, to recognize and treat this infection early and before it spreads, Karakousis says.

Discovery in plant virus may help prevent HIV and similar viruses

Tue, 31 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) WEST LAFAYETTE, Ind. - In a study that could lead to new ways to prevent infection by human immunodeficiency virus (HIV) and similar organisms, Purdue University researchers have been able to genetically modify a plant to halt reproduction of a related virus.

Cauliflower mosaic virus attacks a group of plants that includes the largest number of agriculturally important plants in the world. The plant virus and HIV, which causes AIDS, use the same process to multiply in their victims' cells and spread disease.

After HIV infects a person, it must recruit and latch onto particular human proteins so that the virus can replicate throughout the body, said Zhixiang Chen, a Purdue professor of botany and plant pathology. We found that cauliflower mosaic virus relies on the same protein complex to multiply in plants.

Cauliflower mosaic virus, known as CaMV, attacks a plant group that includes cauliflower, broccoli, cabbages, turnips, canola and many types of mustard.

We believe that the proteins in these host plants might be particularly important for these types of viruses, such as HIV, because if you block them, then the viruses simply can't replicate.

The retrovirus HIV and the pararetrovirus CaMV both use reverse transcription to recruit the host's proteins in order to reproduce and spread infection. Transcription in cells is the process in which a gene's DNA code is copied into RNA, which, in turn, carries the information to another part of the cell or to another cell. In reverse transcription, used by viruses such as HIV and CaMV, the virus' RNA is copied into DNA after it latches on to a victim's cell. This allows the virus to easily integrate into the host's genome and then reproduce in other cells.

Chen and his colleagues published a report on their study in the most recent issue of the journal The Plant Cell.

The researchers found that in the laboratory research plant Arabidopsis, cauliflower mosaic virus recruits a protein complex called CDKC. This is the same protein complex that HIV uses, known in humans as P-TEFb. Since both viruses use this same process to trigger transcription, the scientists now know that this protein complex and its related genes have passed from species to species as organisms evolved over millions of years, Chen said.

P-TEFb appears to be an evolutionarily conserved target of complex retro- and pararetroviruses for activating transcription, he said. This must also reflect a fundamental mechanism for transcription inherited by these viruses.

Humans and organisms used for research, such as fruit flies and the tiny wormlike organism Caenorhabditis elegans, have only one gene in the protein complex that retroviruses use to activate transcription. These organisms die if that gene is completely blocked because of its essential role during transcription. This makes it difficult to analyze the function the gene may have in the organisms' growth, development and survival. Unlike those other organisms, the plant protein complex involves two genes.

In Arabidopsis there are two genes for the CDKC protein complexes that trigger the transcription process, Chen said. If we knock out one of these genes, the plants become resistant to CaMV and the plant is still growing.

The discovery of these two genes suggests that the mustard plant Arabidopsis is a better organism than others for studying how the proteins regulate gene function and transcription, he said.

However, blocking of one of the plant's genes caused some alteration of leaves, flowers and trichomes (tiny hairlike structures) and delayed flowering on the mutated plants, he said. In addition, mutant plants in which both genes were blocked died in the embryonic stage just as would an organism with only one gene.

Now that Chen knows that Arabidopsis has two genes involved in the transcription process, his research team wants to learn more about genes' possible roles in plant growth and development and where those tasks are performed.

The two genes each may have specialized functions depending on where they are activated in the plant, he said. In some tissues the genes appear to be turned on in the same place. But, for example, in the flower, one gene is expressed in one particular place and the other gene is expressed in a different place.

The key question for researchers is how blocking the function of one protein inhibits transcription and replication of the viruses. Discovering the answer could mean major advances for prevention of retroviruses and treatment of the diseases they cause in plants and animals.

Sex-trafficked girls and women from south Asia have high prevalence of HIV infection

Tue, 31 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Nearly 40 percent of repatriated Nepalese sex-trafficked girls and women tested were positive for HIV infection, with girls trafficked before age 15 having higher rates of infection, according to a study in the August 1 issue of JAMA, a theme issue on violence and human rights.

Trafficking across or within national borders for purposes of sexual exploitation including forced prostitution, i.e., sex trafficking, is recognized as a major gender-based human rights violation with significant individual and public health consequences and is increasingly discussed as a potentially critical mechanism in the spread of human immunodeficiency virus (HIV) across developing nations, the authors write.

There are an estimated 150,000 girls and women trafficked each year within and across the countries of South Asia, with approximately 5,000 to 7,000 Nepalese girls and women trafficked to Indias commercial sex industry each year, according to background information in the article. Data on HIV prevalence among survivors of sex trafficking and roles of trafficking-related exposures in HIV infection have been limited.

Jay G. Silverman, Ph.D., of the Harvard School of Public Health, Boston, and colleagues examined the prevalence and risk factors for HIV infection among 287 repatriated Nepalese girls and women sex trafficked to brothels in India. Medical and case records were reviewed of the girls and women, who received rehabilitative services between January 1997 and December 2005.

The researchers found that among the 287 girls and women, 38.0 percent tested positive for HIV. Among those with complete documentation of trafficking experiences (n = 225), median (midpoint) age at time of trafficking was 17.0 years, with 33 girls (14.7 percent) trafficked prior to age 15 years. Compared with those trafficked at 18 years or older, girls trafficked prior to age 15 years had an increased risk for HIV, with 20 of 33 (60.6 percent) infected among this youngest age group.

Additional factors associated with being HIV positive included being trafficked to Mumbai (Indias second largest city) and longer duration of forced prostitution (indicating increased risk per additional month in a brothel). Additional analyses indicated that girls trafficked prior to age 15 years had five times the increased odds of having been detained in multiple brothels and more likely to be in brothels for a duration of 1 year or more vs. those trafficked at age 18 years or older.

The authors write, Findings of the present study emphasize the critical need to strengthen efforts to prevent sex trafficking and to intervene to protect trafficking survivors so as to shield young girls and women, both from this form of sexual violence and from the high risk of HIV infection. Currently, relatively few such efforts exist, and organizations that do engage in this work often lack adequate political or financial support. Furthermore, the high rates of HIV documented herein support concerns that sex trafficking may be a significant factor in the expansion of the South Asian HIV epidemic, both within higher-prevalence nations such as India and also from such nations to their lower-prevalence neighbors (e.g., Nepal). Moreover, the current demonstration of the very young age of many of those trafficked and sexually exploited, and the further harm to these young lives through high rates of HIV infection, requires attention from public health researchers and strategists to better understand and reduce the demand for sexual services from prostituted girls and women.