Antiretroviral Drugs May Protect Against Sexual Transmission Of HIV

Daily Science Journal (Feb. 12, 2008) — A new study in macaques suggests that antiretroviral drugs used to treat HIV could also protect people from getting the AIDS virus, especially if two drugs are taken in combination before exposure to the virus occurs.

A new study in macaques suggests that antiretroviral drugs used to treat HIV could also protect people from getting the AIDS virus, especially if two drugs are taken in combination before exposure to the virus occurs. (Credit: iStockphoto/Claire George)

The study found that macaques which were repeatedly exposed to SHIV (a virus closely related to HIV) but received antiretroviral drugs were less likely to become infected than exposed macaques that received no anti-HIV medication. The best protection was seen in macaques that had received a combination of two drugs. The study, led by José Gerardo García-Lerma and Walid Heneine from the US Centers for Disease Control and Prevention, is the culmination of a series of experiments designed to show how similar studies in humans -- some of which are planned and in progress -- can be optimally designed.

Although HIV treatment has rapidly advanced since the introduction of antiretroviral drugs in the 1990s, the absence of an effective vaccine means the virus continues to spread, infecting 2.5 million people each year. Pre-exposure prophylaxis (PrEP) -- the prevention of infection by treating people with drugs before they are exposed to the germ in question -- is often used to prevent malaria, but has not yet been shown to be effective against sexual transmission of HIV.

To simulate a common route of HIV transmission in humans, the researchers exposed the macaques to low weekly doses of SHIV that were given rectally. Five groups of macaques were all exposed to the virus in the same way, but they were given different dosages and combinations of antiretroviral drugs. Three groups received drugs daily: the first was only injected with one anti-HIV drug, emtricitabine (FTC); the second group received a daily dose of this drug by mouth in combination with an oral form of another anti-HIV drug called tenofovir; the third was injected with FTC and a high dose of tenofovir every day. A fourth group was also injected with FTC and a high dose of tenofovir, but macaques in this group were only treated shortly before and after the weekly exposures to HIV. For comparison a fifth group of macaques received no anti-HIV drugs.

The results showed that macaques from any of the four groups that received drugs were less likely to become infected than those in the fifth (control) group. All of the macaques receiving the combination of both FTC and the high dosage of tenofovir were protected from infection -- whether they were from the group that received these drugs daily, or only around the time of exposure to infection. The results suggest that higher doses and combinations of drugs worked better than single or low doses, and also that PrEP may not need to be taken every day to be effective.

The researchers also observed some risks that emphasize the need for careful design of human PrEP studies. They found some viral resistance to one of the drugs, FTC, in macaques that became infected. In addition, doses of tenofovir that resulted in maximum protection for macaques are higher than would be safe in humans.

In a related perspective article, Myron Cohen and Angela Kashuba from the University of North Carolina (Chapel Hill, NC, USA), uninvolved with the study, note that the results "highlight an exciting and potentially important use" of antiretroviral drugs to prevent sexual transmission of HIV.

Journal citation: García-Lerma JG, Otten RA, Qari SH, Jackson E, Cong M, et al. (2008) Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 5(2): e28. doi:10.1371/journal.pmed.0050028 http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050028

Adapted from materials provided by Public Library of Science, via EurekAlert!, a service of AAAS.

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Herpes Medication Does Not Reduce Risk Of HIV Infection In Individuals With HSV-2, Study Finds

Daily Science Journal (Feb. 10, 2008) — An international clinical trial has found that acyclovir, a common medication for treating herpes simplex virus-2 (HSV-2), the most common cause of genital herpes, does not reduce the risk of HIV infection when taken by people infected with HSV-2. Multiple studies have shown that people with HSV-2 have a higher risk of acquiring HIV. Researchers had hoped that acyclovir's ability to suppress the herpes virus, and its associated genital sores and breaks in the skin, could cut down on the likelihood of HIV being transmitted to a person with HSV-2 during sexual intercourse.

The Phase III clinical trial was led by the University of Washington in Seattle, in coordination with the HIV Prevention Trials Network, an international consortium funded by the National Institute of Allergy and Infectious Diseases (NIAID) in the National Institutes of Health. The findings were presented this week at the Conference on Retroviruses and Opportunistic Infections in Boston.

"The study was successful in answering the question of whether acyclovir could cut down on the risk of HIV acquisition for people infected with HSV-2," explained Dr. Connie Celum, the leader of the study and a UW professor of global health and medicine in the Division of Allergy and Infectious Disease and director of the International Clinical Research Center in the UW Department of Global Health. "We were hopeful that acyclovir would help reduce HIV acquisition in people with HSV-2. Though the study did not find that acyclovir helped with HIV acquisition, we did find that it reduced genital ulcers associated with HSV-2. Now we need to continue our research on the mechanisms through which HSV-2 acts as a risk factor for HIV, and how we might be able to use that knowledge to reduce the spread of HIV."

HSV-2 is one of the most common sexually transmitted infections worldwide and is especially prevalent in areas with high rates of HIV infection. Most people who are infected with HSV-2 do not know they have the virus because symptoms can be mild or absent. In some infected individuals, the virus can produce recurring genital herpes, a condition characterized by sores and breaks in the skin of the genital region. An active HSV-2 infection also attracts immune-system cells called CD-4 T-cells to the genital region, and HIV easily attaches to this type of cell. Multiple studies have shown that people with HSV-2 have a two-fold increase in their risk of acquiring HIV.

This study followed up on those results to test the theory that suppressing HSV-2 could cut down on HIV acquisition. It was launched in 2003, and with nine study sites in Peru, South Africa, Zambia, Zimbabwe, and the United States, it was the largest study yet of herpes suppression. There were 3,277 people with HSV-2 initially enrolled in the study, 105 people excluded, and 3,172 people included in the final analysis. Volunteers in Peru and the United States were HSV-2-infected men who have sex with men, and volunteers in Africa were HSV-2-infected women.

Half of the participants were randomly assigned to receive either a placebo or a standard daily dose of acyclovir, 400 mg twice a day. The study was double-blinded, meaning that neither participants nor care providers knew which treatment the participants were receiving. Both the placebo and treatment groups received standard HIV-prevention treatment, which includes being supplied with condoms and given extensive counseling on how to reduce the risk of HIV infection.

Researchers found that there was a 3.9 percent HIV incidence rate, a total of 75 cases, in participants who received acyclovir suppression, and a 3.3 percent HIV incidence rate, or 64 cases, in the placebo group. The difference between the groups was not statistically significant. The acyclovir treatment did succeed in reducing genital ulcers -- participants in the treatment group had a 37 percent reduction in genital ulcer incidence, and a significantly lower proportion of ulcers due to HSV-2.

"The study answered the scientific questions it was designed to answer," says Dr. Anna Wald, a UW professor of medicine and epidemiology who also helped lead the study. "The sites were able to recruit and retain a large number of volunteers, who maintained a high level of adherence to the twice-daily drug regimen. While we are disappointed with the results, the study was well-conducted and provides a clear answer about using acyclovir to reduce the risk of becoming HIV-infected."

The study participants have been informed of the findings and are being counseled on the continued need to avoid HIV exposure. Volunteers who became infected with HIV during the trial have been referred for appropriate medical care and treatment.

The study was supported by NIAID, and the acyclovir was supplied by GlaxoSmithKline. The HIV Prevention Trials Network is led by Family Health International, the network laboratory of Johns Hopkins University, and the Statistical Center for HIV/AIDS Research and Prevention at the Fred Hutchinson Cancer Research Center in Seattle. The study was conducted at the following sites: Iquitos, Lima and Pucallpa, in Peru; Johannesburg, South Africa; New York, San Francisco, and Seattle, in the United States; Lusaka, Zambia; and Harare, Zimbabwe.

Adapted from materials provided by University Of Washington.

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Virtual Human In HIV Drug Simulation

Daily Science Journal (Feb. 2, 2008) — The combined supercomputing power of the UK and US ‘national grids’ has enabled UCL (University College London) scientists to simulate the efficacy of an HIV drug in blocking a key protein used by the lethal virus. The method – an early example of the Virtual Physiological Human in action – could one day be used to tailor personal drug treatments, for example for HIV patients developing resistance to their drugs.

The study ran a large number of simulations to predict how strongly the drug saquinavir would bind to three resistant mutants of HIV-1 protease, a protein produced by the virus to propagate itself. These protease mutations are associated with the disease’s resistance to saquinavir, an HIV-inhibitor drug.

The study, by Professor Peter Coveney and colleagues at the UCL Department of Chemistry, involved a sequence of simulation steps, performed across several supercomputers on the UK’s National Grid Service and the US TeraGrid, which took two weeks and used computational power roughly equivalent to that needed to perform a long-range weather forecast.

The idea behind the Virtual Physiological Human (VPH) is to link networks of computers across the world to simulate the internal workings of the human body. The VPH – mainly a research initiative at present – allows scientists to simulate the effects of a drug and see what is happening at the organ, tissue, cell and molecular level.

Although nine drugs are currently available to inhibit HIV-1 protease, doctors have no way of matching a drug to the unique profile of the virus as it mutates in each patient. Instead, they prescribe a course of drugs and then test whether these are working by analysing the patient’s immune response. One of the goals of VPH is for such ‘trial and error’ methods to eventually be replaced by patient-specific treatments tailored to a person’s unique genotype.

Professor Peter Coveney says: “This study represents a first step towards the ultimate goal of ‘on-demand’ medical computing, where doctors could one day ‘borrow’ supercomputing time from the national grid to make critical decisions on life-saving treatments.

“For example, for an HIV patient, a doctor could perform an assay to establish the patient’s genotype and then rank the available drugs’ efficacy against that patient’s profile based on a rapid set of large-scale simulations, enabling the doctor to tailor the treatment accordingly.

“We have some difficult questions ahead of us, such as how much of our computing resources could be devoted to helping patients and at what price. At present, such simulations – requiring a substantial amount of computing power – might prove costly for the National Health Service, but technological advances and those in the economics of computing would bring costs down.”

For the moment, Professor Coveney’s group is continuing to look at all the protease inhibitors in a similar way. The VPH initiative, now underway with 72 million euros of initial funding from the EU, will boost collaboration between clinicians and scientists to explore the scope for patient-specific medical treatments based on modern modelling and simulation methods.

Journal reference: ‘Rapid and Accurate Prediction of Binding Free Energies for Saquinavir-Bound HIV-1 Proteases’, by Ileana Stoica, S. Kashif Sadiq, and Peter V. Coveney, is published online in the Journal of the American Chemical Society on Tuesday 29 January 2008.

The study was partially funded by the EPSRC, the EU-supported ViroLab project and the National Science Foundation. The UK National Grid Service also provided access to their resources and support for this project.

Adapted from materials provided by University College London.

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How Poxviruses Such As Smallpox Evade The Immune System

Daily Science Journal (Feb. 1, 2008) — Scientists at Saint Louis University and the University of Alabama at Birmingham have uncovered important new information about a key protein that allows viruses such as smallpox to replicate and wreak havoc on the immune system.

The findings further our understanding of how the pox family of viruses work to subvert the immune system, the researchers say. They also believe their work could one day be used to develop new drugs to combat a variety of inflammatory and immunological disorders, including rheumatoid arthritis and some forms of heart disease.

The paper* describes the structure and actions of a powerful substance called interferon-gamma binding protein, which is notorious for the role it plays in helping the poxviruses to replicate. The research explores the interferon-gamma binding protein found in the mousepox virus -- one of the family of viruses that also includes smallpox, monkeypox and cowpox.

"Cracking open and describing the structure and actions of interferon-gamma binding protein is incredibly exciting, given the important role this substance plays in subverting the immune system," said Mark Buller, Ph.D., professor of microbiology and immunology at the Saint Louis University School of Medicine and one of the study's authors. "This breakthrough is something that many others have tried and failed to achieve."

Normally when a virus enters the bloodstream, the immune system responds by producing a substance called interferon-gamma, which assists the development of the immune response that's responsible for ridding the body of the virus.

Poxviruses, however, all come encoded with a potent weapon to evade the immune system: interferon-gamma binding protein. As its name implies, the protein literally binds to interferon-gamma and immobilizes it, preventing it from marshalling the immune system's defenses. The poxvirus is then able to replicate and cause immense damage.

The research describes how interferon-gamma binding protein looks and behaves on the molecular level during this process, something not previously understood.

"The poxviruses are able to evade the immune system very skillfully," Buller said, "so we wanted to identify exactly how these viruses work -- what makes them so effective and efficient."

Buller added that the findings have great potential for use in developing drugs that target immunological and inflammatory disorders, including a type of heart disease called atherosclerosis (sometimes referred to as hardening of the arteries), inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis) and rheumatoid arthritis.

Of all the poxviruses, smallpox in particular has played a gruesome role in human history. The virus is estimated to have caused between 300 million and 500 million deaths in the 20th century alone. Though smallpox was declared officially eradicated in 1979, many experts fear that clandestine samples of the virus may have survived -- thus making it a major bioterrorism concern.

"The damage that the smallpox virus has done to mankind is horrific and enormous, which is why we think it's so important to understand more about the poxviruses and how they operate," Buller said. "The more knowledge we have, the better we should be able to cope with other major viruses and diseases in the future."

Buller pointed to co-author Tony Nuara as being critical to the team's success in understanding more about interferon-gamma binding protein. Nuara, now a fourth-year student at Saint Louis University School of Medicine, was working on his Ph.D. in molecular microbiology when taking part in the research effort.

"Without Tony, this research wouldn't have happened," Buller said. "He solved huge numbers of problems and figured out some answers to puzzling questions that previously had no answer."

Mark R. Walter, Ph.D., associate professor of microbiology at the University of Alabama at Birmingham and the paper's senior author, also noted the efforts of co-authors Sung Il Yoon, Ph.D., Brandi C. Jones, Naomi J. Logsdon and Leigh J. Walter, all of whose work contributed to determining the three-dimensional structure of the binding protein.

"The structure provides a visual blueprint to guide our future studies on interferon-gamma binding protein, which one day may be used to prevent inflammatory disease," Mark Walter said. "This is clearly a notable achievement."

*The research has been published in an early online edition of the Proceedings of the National Academy of Sciences. Jill M. Schriewer of Saint Louis University was also a co-author of the study.

The research was funded by grants from the National Institutes of Health, the UAB Center for Emerging Infections and Emergency Preparedness, and the American Heart Association.

Adapted from materials provided by Saint Louis University, via EurekAlert!, a service of AAAS.

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