article : Increasing access to antiretroviral drugs would drastically cut AIDS deaths in South Africa

More that 1.2 million deaths could be prevented in South Africa over the next five years by accelerating efforts to provide access to antiretroviral therapy (ART), according to a study released online today by the Journal of Infectious Diseases. Using a sophisticated mathematical model of HIV disease and treatment, a team of researchers led by Rochelle Walensky, MD, MPH of Massachusetts General Hospital (MGH) estimated the number of AIDS-related deaths in South Africa through 2012 under alternative ART scale-up assumptions.

The study results underscore the urgent need for Congress to reauthorize the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), which has supported the South African government’s effort to increase access to antiretroviral therapy, the researchers note. “If ART is not provided to all who need it, HIV mortality will be enormous,” says Walensky. “Deliberate, purposeful, and expedient scale-up will save millions of lives in South Africa alone.”

South Africa has one of the largest burdens of HIV infection in the world, with 5 to 6 million individuals and 19 percent of adults aged 15 to 49 infected. While government programs supported by PEPFAR and the Global Fund to Fight AIDS, Tuberculosis and Malaria have steadily increased access to antiretrovirals, at the end of 2006 only a third of individuals eligible for the therapy were receiving it.

In order to quantify the potential impact of various strategies for increasing access to ART, the research team projected the number of deaths under five scenarios – ranging from maintaining current access levels, through steady and moderate growth levels, to rapid growth and full access for all patients requiring treatment. Among other factors, calculations were based on the fact that the one-year survival rate for eligible patients who receive antiretroviral therapy is 94 percent, while only 55 percent of those not treated would be expected to survive one year.

Results showed that maintaining current treatment capacity would lead to 2.4 million AIDS-related deaths by 2012. Rapid scale-up, whereby everyone in need would have access by 2011, would reduce the projected number of deaths to 1.2 million during that time period, and immediate full access for all eligible patients would drop deaths to 800,000.

The researchers note that efforts to scale up treatment have resulted in a fivefold increase in access to ART in low and moderate-income countries. “Continued investments in antiretroviral treatment programs worldwide are a public health imperative; the potential loss of life without such support is simply unacceptable,” says Walensky, who is an associate professor of Medicine at Harvard Medical School.

Source : Massachusetts General Hospital

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article : Expansion of monocyte subset could serve as a biomarker for HIV progressions

An increase in the CD163+/CD16+ monocyte subset could be a biomarker for the progression of HIV disease, according to researchers at Temple University.

The researchers reported their findings, “CD163/CD16 Coexpression by Circulating Monocytes/Macrophages in HIV: Potential Biomarkers for HIV Infection and AIDS Progression,” in the March issue of AIDS Research and Human Retroviruses (www.liebertonline.com/aid).

A monocyte is a specific white blood cell, a part of the human body’s immune system that protects against blood-borne pathogens and moves quickly to sites of infection within the body’s tissues. As monocytes enter tissue, they undergo a series of changes to become macrophages.

The researchers were investigating alterations in this monocyte subset in patients with HIV infection. As part of this study, they examined a cohort of 18 patients from the Comprehensive HIV Program at Temple University Hospital, under the direction of Ellen Tedaldi, and seven individuals without HIV infection.

“At first, we were just looking at whether or not we saw alterations in this CD163+/CD16+ subset and whether it might be reflective of the amount of virus they have in circulation,” said Tracy Fischer-Smith, an associate scientist in Temple’s Neuroscience Department and the study’s lead author. “We did, indeed, find that patients with detectable virus had an increase of this monocyte subset that correlated with the amount of virus they had in their blood. We were surprised to find that patients with CD4+ T cell counts of less than 450 cells per microliter [200 or less per microliter is defined as AIDS], the increase of this monocyte subset correlates inversely with the number of T cells.”

Fischer-Smith said this finding suggests that as the monocyte cells are increasing, these patients are losing CD4+ T cells, which are critical for the maintenance of immunological competence.

“This may actually provide an earlier window into what is happening with HIV-infected patients where we might be able to see that immune impairment is taking place before we see a dramatic loss of CD4+ T cells,” she said.

“It looks like, based on these correlations, that this particular cell type may be involved in immune impairment and the progression of HIV,” said Jay Rappaport, professor of neuroscience and neurovirology, who oversaw the study. “Is it a good prognostic indicator" If you have a lot of these monocytes, does it mean you are going to progress into AIDS faster" “Right now, all we know is what the correlations are,” he said.

Rappaport added that he believes the CD163+/CD16+ monocyte subset is the first biomarker that correlates with viral load and CD4+ count. “The fact that it actually correlates with both, we think, might make it a key cell type in the pathogenesis of AIDS.” Fischer-Smith said the researchers plan to expand this study by following a cohort of patients longitudinally to see if their findings really can provide doctors with an early warning system and help to design better therapeutic strategies.

“When you are just looking at a single time-point, you don’t know how changes in this monocyte subset might occur over time, and how these changes might relate to the viral load and T cell number in individual patients,” she said. “That is why we want to investigate this further with a longitudinal study of HIV patients.”

Source : Temple University

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article : Clinical trial will test new HIV/AIDS vaccine

A phase 1 clinical trial to test a novel HIV/AIDS vaccine has begun at Brigham and Women’s Hospital (BWH). This new vaccine aims to overcome the problem of preexisting immunity to common vaccine vectors, which is thought to be a major problem in the developing world.

“This study will involve 48 healthy volunteers who will receive either two or three immunizations and who will be followed to assess the safety and immunogenicity of the vaccine,” explains Lindsey R. Baden, MD, Assistant Professor of Medicine at BWH and Harvard Medical School and Protocol Chair for the study.

The vaccine consists of a replication-incompetent, recombinant adenovirus serotype 26 (rAd26) vector encoding an HIV-1 envelope gene.

“The rAd26 vaccine vector was selected for its particularly low seroprevalence in human populations and for its potent immunogenicity and protective efficacy in preclinical studies,” explains Dan H. Barouch, MD, PhD, Associate Professor of Medicine at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School and Principal Investigator of the Integrated Preclinical/Clinical AIDS Vaccine Development (IPCAVD) program that developed the vaccine. This program is sponsored by the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Manufactured by the Dutch biotechnology company Crucell Holland BV, the rAd26 vaccine is the first HIV-1 vaccine candidate to emerge from the IPCAVD initiative, which brings together investigators from academia and industry in an effort to accelerate the development of promising HIV/AIDS vaccine candidates. The novel strategy used in developing this vaccine enables researchers to circumvent preexisting immunity to the adenovirus serotype 5, the virus responsible for the common cold, which has recently shown limitations as an HIV-1 vaccine vector.

“The rAd26 vector does not regularly occur in the human population and human antibodies to this vector are rare,” explains Jaap Goudsmit, Chief Scientific Officer at Crucell. “The rAd26 vector therefore is efficacious in eliciting good T and B cell responses.”

AIDS remains one of the world’s most devastating health problems, with an estimated 33.2 million people living with HIV/AIDS and 2.5 million new infections reported in 2007 alone.

Source : Beth Israel Deaconess Medical Center

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article : Leading HIV researchers to collaborate on vaccine development

Two global research organizations dedicated to designing a vaccine against HIV – the International AIDS Vaccine Initiative (IAVI), and the Center for HIV/AIDS Vaccine Immunology (CHAVI) – have signed an agreement to work together to address major biological questions that have slowed development of a safe, effective and affordable AIDS vaccine.

“Solving the HIV vaccine puzzle is a scientific challenge that can only be solved through fundamental and applied research, collaboration and transparency. The work that will be done by IAVI, CHAVI and their networks of partners will rapidly enhance our understanding of HIV and help lay the groundwork for new vaccine approaches,” says Dr. Barton Haynes, CHAVI director and professor of medicine at Duke University Medical Center.

There are approximately 33 million people around the world living with HIV, the virus that causes AIDS. Scientists have tested multiple vaccine candidates in early phase trials, but only two have been fully tested in efficacy trials and neither has been found effective in preventing HIV infection or lowering the viral load in patients who subsequently encountered HIV and became infected.

“We are committed to the discovery of an effective vaccine, particularly for regions hardest hit by the epidemic,” says Dr. Wayne Koff, senior vice president of research and development at IAVI. “We are hoping that the synergy of shared investigation will yield insight into novel solutions that will advance AIDS vaccine discovery.”

The shared CHAVI/IAVI research mission will focus on four key areas that will help inform the design of new and improved vaccine candidates:

• Identification and full-length genetic sequencing of newly transmitted viruses
• Clarifying the impact of human genetics on the control of HIV infection
• Collaborative immunological studies that could shed light on why some people who are exposed to HIV do not develop AIDS
• Development of standardized methods to sample tissues from mucosal surfaces in the body, where HIV initially establishes infection.

Investigators supported by both organizations are especially interested in further understanding what happens in the very earliest post-infection stage of HIV infection, especially within the body’s T cells, a class of white blood cells that normally fight off foreign invaders like bacteria and viruses. One of the goals of this work will be to identify any genetic variations linked to the strength of the immune response at the site of initial infection. CHAVI and IAVI hope that by sharing samples, reagents, databases and laboratories and by launching parallel studies, they will be able to speed up discoveries about this critical phase of the disease.

Each partner to the agreement will contribute unique resources. For example, CHAVI supports high-throughput sequencing technology that can reveal tiny mutations in the ever-changing virus, but which require large numbers of HIV samples in order to identify variations that are meaningful. Through its network of clinical research centers and immunological laboratories around the world, IAVI and its partners have developed a number of tests to evaluate human immune responses to HIV and to potential vaccine candidates, information that can help researchers refine and improve any candidate that shows promise. By pooling technologies, protocols and access to samples, the IAVI/CHAVI collaboration aims to extract maximum information to help accelerate the development of a safe and effective AIDS vaccine.

“As an African clinical investigator and the leader of the scientific steering committee that oversees the IAVI-supported study of acute HIV infection, I am pleased to be collaborating with IAVI and CHAVI. It is critical to investigate the influence of genetic diversity of HIV as well as the variety of human immune responses to HIV among populations that are hardest hit by the epidemic,” said Dr. Pontiano Kaleebu, assistant director and a Principal Investigator at the Uganda Virus Research Institute.

“Now, more than ever, we need to understand the complexities of HIV and the genes that control the human immune response to it,” says Dr. Alan Bernstein, recently appointed as the first executive director of the Global HIV/AIDS Vaccine Enterprise. The Enterprise was established to accelerate development of a safe and effective HIV vaccine through encouraging collaboration within the HIV vaccine research field. “This new collaboration holds great promise in accelerating our basic understanding of HIV and will form the necessary underpinnings needed to develop a vaccine,” Bernstein added.

Source : Duke University Medical Center

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article : The new research findings open new front in fight against AIDS virus

A research group supported by the National Institutes of Health (NIH) has uncovered a new route for attacking the human immunodeficiency virus (HIV) that may offer a way to circumvent problems with drug resistance. In findings published today in the online edition of the Proceedings of the National Academy of Sciences, the researchers report that they have blocked HIV infection in the test tube by inactivating a human protein expressed in key immune cells.

Most of the drugs now used to fight HIV, which is the retrovirus that causes acquired immune deficiency syndrome (AIDS), target the virus’s own proteins. However, because HIV has a high rate of genetic mutation, those viral targets change quickly and lead to the emergence of drug-resistant viral strains. Doctors have tried to outmaneuver the rapidly mutating virus by prescribing multi-drug regimens or switching drugs. But such strategies can increase the risk of toxic side effects, be difficult for patients to follow and are not always successful. Recently, interest has grown in attacking HIV on a new front by developing drugs that target proteins of human cells, which are far less prone to mutations than are viral proteins.

In the new study, Pamela Schwartzberg, M.D., Ph.D., a senior investigator at the National Human Genome Research Institute (NHGRI), part of NIH; Andrew J. Henderson, Ph.D., of Boston University; and their colleagues found that when they interfered with a human protein called interleukin-2-inducible T cell kinase (ITK) they inhibited HIV infection of key human immune cells, called T cells. ITK is a signaling protein that activates T cells as part of the body’s healthy immune response.

“This new insight represents an important contribution to HIV research,” said NHGRI Scientific Director Eric D. Green, M.D., Ph.D. “Finding a cellular target that can be inhibited so as to block HIV validates a novel concept and is an exciting model for deriving potential new HIV therapies.”

When HIV enters the body, it infects T cells and takes over the activities of these white blood cells so that the virus can replicate. Eventually, HIV infection compromises the entire immune system and causes AIDS. The new work shows that without active ITK protein, HIV cannot effectively take advantage of many signaling pathways within T cells, which in turn slows or blocks the spread of the virus.

“We were pleased and excited to realize the outcome of our approach,” Dr. Schwartzberg said. “Suppression of the ITK protein caused many of the pathways that HIV uses to be less active, thereby inhibiting or slowing HIV replication.”

In their laboratory experiments, the researchers used a chemical inhibitor and a type of genetic inhibitor, called RNA interference, to inactivate ITK in human T cells. Then, the T cells were exposed to HIV, and the researchers studied the effects of ITK inactivation upon various stages of HIV’s infection and replication cycle. Suppression of ITK reduced HIV’s ability to enter T cells and have its genetic material transcribed into new virus particles. However, ITK suppression did not interfere significantly with T cells’ normal ability to survive, and mice deficient in ITK were able to ward off other types of viral infection, although antiviral responses were delayed.

“ITK turns out to be a great target to examine,” said Dr. Schwartzberg, noting that researchers had been concerned that blocking other human proteins involved in HIV replication might kill or otherwise impair the normal functions of T cells.

According to Dr. Schwartzberg, ITK already is being investigated as a therapeutic target for asthma and other diseases that affect immune response. In people with asthma, ITK is required to activate T cells, triggering lung inflammation and production of excess mucus.

“There are several companies who have published research about ITK inhibitors as part of their target program,” Schwartzberg said. “We hope that others will extend our findings and that ITK inhibitors will be pursued as HIV therapies.”

Source : NIH/National Human Genome Research Institute

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article : How we know climate change threats to HIV rates

Social factors, including economic pressures caused by climate change, could lead to an increase in HIV infection rates world-wide, warns a leading researcher from the University of New South Wales (UNSW).

Daniel Tarantola, Professor of Health and Human Rights at the School of Public Health and Community Medicine, says that disadvantage in developing countries must be addressed if the world is to prevent a dramatic escalation of the HIV epidemic as well as other health problems.

Professor Tarantola will join a panel of top HIV researchers to address the topic “A Future Free of HIV” at UNSW on Wednesday night. The event will be moderated by the Honourable Justice Michael Kirby AC.

“It was clear soon after the emergence of the HIV epidemic that discrimination, gender inequality and lack of access to essential services have made some populations more vulnerable than others. These problems have not gone away,” Professor Tarantola says.

“Today, additional threats are lurking on the horizon as the global economic situation deteriorates, food scarcity worsens and climate change begins to affect those who were already dependent on survival economies.

“The same is true for climate change. Climate change will trigger a chain of events which is likely to increase the stress on society and result in higher vulnerability to diseases including HIV,” he says.

Professor David Cooper AO, Director of UNSW’s National Centre in HIV Epidemiology and Clinical Research (NCHECR) says: “Science has achieved great strides towards shaping a more effective response to HIV. Yet research has not succeeded in producing the hoped-for ‘magic bullets’ of either a cure or a vaccine.

“We need to escalate our research efforts while sustaining and expanding what we know works: good prevention and access to life-saving antiretroviral therapy and integrated care.”

Source : Research Australia

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As HIV disease progresses in a person infected with the HIV virus, a group of cells in the immune system, the CD8+ T lymphocytes, become “exhausted,” losing many of their abilities to kill other cells infected by the virus. For many years scientists have debated whether this exhaustion of CD8+ T cells is the cause, or the consequence, of persistence of the HIV virus. In a study published this week in PLoS Medicine, Marcus Altfeld and colleagues studied the immune response over time amongst 18 individuals who had very recently become infected with HIV.

These researchers found that the presence of high amounts of HIV in the blood seemed to cause CD8+ T cell exhaustion; when antigen was reduced, either as a result of treatment with antiretroviral drugs, or evolution of viral epitopes to avoid recognition by CD8+ T cells, these epitope-specific CD8+ T cells recovered some of their original functions. These findings suggest that CD8+ T cell exhaustion is the consequence, rather than the cause, of persistent replication of HIV.

In a related article, Sarah Rowland-Jones and Thushan de Silva (from the Medical Research Council in Gambia), who were not involved in the study, discuss approaches to treat HIV efficiently by suppressing the viral load early in infection aimed at preserving HIV-1-specific immune function. They evaluate whether such strategies are likely to be practical.

Citation: Streeck H, Brumme ZL, Anastario M, Cohen KW, Jolin JS, et al. (2008) Antigen load and viral sequence diversification determine the functional profile of HIV-1– specific CD8þ T cells. PLoS Med 5(5):e100.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE

VERSIONS OF YOUR REPORT: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/
journal.pmed.0050100

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-05-05-altfeld.pdf

CONTACTS:
Sue McGreevey
Public Affairs Office
Massachusetts General Hospital
Boston, MA
+1 617 724-2764
smcgreevey@partners.org

Marcus Altfeld
Massachusetts General Hospital
Partners AIDS Research Center
149 13th Street
Boston, MA 02129
United States of America
+1 617-724-2461
+1 617-724-8586 (fax)
maltfeld@partners.org

---

Related PLoS Medicine Research in Translation:

Citation: Rowland-Jones S, de Silva T (2008) Resisting immune exhaustion in

HIV-1 infection. PLoS Med 5(5): e103.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE

VERSIONS OF YOUR REPORT: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/
journal.pmed.0050103

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-05-05-rowland-jones.pdf

CONTACT:
Sarah Rowland-Jones
Weatherall Institute of Molecular Medicine
MRC Human Immunology Unit
Radcliffe Hospital
Headley Way
Oxford, OX3 9DS
United Kingdom
+44 (1865) 222 316
+44 (1865) 222 502 (fax)
sarah.rowland-jones@ndm.ox.ac.uk

---

THE FOLLOWING ARTICLE WILL ALSO BE PUBLISHED ONLINE:

Hypofibrinolysis and other risk factors for first venous thrombosis

Frits Rosendaal and colleagues from Leiden University Medical Center
show that the combination of hypofibrinolysis with oral contraceptive use,
immobilization, or factor V Leiden results in a risk of venous thrombosis
that exceeds the sum of the individual risks.

Citation: Meltzer ME, Lisman T, Doggen CJM, de Groot PG, Rosendaal
FR (2008) Synergistic effects of hypofibrinolysis and genetic and acquired risk factors on

the risk of a first venous thrombosis. PLoS Med 5(5): e97.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE

VERSIONS OF YOUR REPORT: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/
journal.pmed.0050097

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-05-05-rosendaal.pdf

CONTACTS:
Frits R. Rosendaal
Leiden University Medical Center
Clinical Epidemiology and Hematology
PO Box 9600
Leiden, 2300 RC
Netherlands
+31 715 264 037
f.r.rosendaal@lumc.nl

Source : Public Library of Science

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article : Molecular espionage shows a single HIV enzyme's many tasks

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.

Source : Harvard University

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article : Compound has potential for new class of AIDS drugs

Researchers have developed what they believe is the first new mechanism in nearly 20 years for inhibiting a common target used to treat all HIV patients, which could eventually lead to a new class of AIDS drugs.

Researchers at the University of Michigan used computer models to develop the inhibiting compound, and then confirmed in the lab that the compound does indeed inhibit HIV protease, which is an established target for AIDS treatment. The protease is necessary to replicate the virus, says Heather Carlson, U-M professor of medicinal chemistry in the College of Pharmacy, and principal investigator of the study.

Carlson stresses this is a preliminary step, but still significant.

"It's very easy to make an inhibitor, (but) it's very hard to make a drug," said Carlson, who also has an appointment in chemistry. "This compound is too weak to work in the human body. The key is to find more compounds that will work by the same mechanism."

What's so exciting is how differently that mechanism works from the current drugs used to keep the HIV from maturing and replicating, she says. Current drugs called protease inhibitors work by debilitating the HIV-1 protease. This does the same, but in a different way, Carlson says.

A protease is an enzyme that clips apart proteins, and in the case of HIV drugs, when the HIV-1 protease is inhibited it cannot process the proteins required to assemble an active virus. In existing treatments, a larger molecule binds to the center of the protease, freezing it closed.

The new mechanism targets a different area of the HIV-1 protease, called the flap recognition pocket, and actually holds the protease open. Scientists knew the flaps opened and closed, but didn't know how to target that as a mechanism, Carlson says.

Carlson's group discovered that this flap, when held open by a very small molecule---half the size of the ones used in current drug treatments---also inhibits the protease.

In addition to a new class of drugs, the compound is key because smaller molecules have better drug-like properties and are absorbed much more easily.

"This new class of smaller molecules could have better drug properties (and) could get around current side effects," Carlson said. "HIV dosing regimes are really difficult. You have to take medicine several times in the day. Maybe you wouldn't have to do that with these smaller molecules because they would be absorbed differently."

Kelly Damm, a former student and now at Johnson & Johnson, initially had the idea to target the flaps in this new way, Carlson says.

"In a way, this works like a door jam. If you looked only at the door when it's shut, you'd not know you could put a jam in it," she said. "We saw a spot where we could block the closing event, but because everyone else was working with the closed form, they couldn't see it."

Source : University of Michigan

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article : Dr. Anthony Fauci has reflects on 25 years of HIV

On the 25th anniversary of the first scientific article linking a retrovirus to AIDS, Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, reflects in an essay in Nature on his experience treating and studying HIV/AIDS for the past quarter century. Outlining the peaks and valleys of the scientific community’s journey so far, Dr. Fauci writes, “…we must learn from our mis-steps, build on our successes in treatment and prevention, and renew our commitment to developing the truly transforming tools that will one day put this scourge behind us.”

From the outset, AIDS was clearly more menacing than any other novel disease Dr. Fauci and his colleagues had previously encountered, he writes. The period when clinicians lacked the ability to diagnose and treat AIDS was the bleakest of his career. The discovery that HIV causes AIDS stimulated a burst of progress in both the clinic and the laboratory. But the 1987 debut of the first effective drug against HIV, zidovudine (AZT), generated excessive optimism, Dr. Fauci reflects, as the virus quickly and predictably developed drug resistance.

Eight years and thousands of AIDS deaths later, protease inhibitors launched a renaissance of anti-HIV drug development in 1995. Combination therapies dramatically cut the rate of AIDS deaths in the United States—but the developing world has continued to suffer from lack of access to effective treatments for HIV. Even more sobering, Dr. Fauci writes, “Treatment alone will never end the AIDS pandemic…around three people are newly infected for every person put on therapy.”

So what options remain? Dr. Fauci praises research aimed at finding a cure for HIV/AIDS and affirms that this work must continue, but he places considerable hope and energy in preventing HIV infection, most importantly through the development of a vaccine. In retrospect, he writes, the scientific community expected to achieve an HIV vaccine unrealistically quickly. He advises that the steps we must take toward this goal now involve basic research, interdisciplinary research and active fostering of innovation, especially among young investigators. Twenty-five years since the discovery of HIV, Dr. Fauci views the prospect of ending the HIV/AIDS pandemic with cautious optimism.

Source : NIH/National Institute of Allergy and Infectious Diseases

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article : HIV infection stems from few viruses

A new study reveals the genetic identity of human immunodeficiency virus (HIV), the version responsible for sexual transmission, in unprecedented detail.

The finding provides important clues in the ongoing search for an effective HIV/AIDS vaccine, said researchers at the University of Alabama at Birmingham (UAB). The UAB team found that among billions of HIV variants only a few lead to sexual transmission.

Earlier studies have shown that a ‘bottleneck’ effect occurs where few versions of the virus lead to infection while many variants are present in the blood. The UAB study is the first to use genetic analysis and mathematical modeling to identify precisely those viruses responsible for HIV transmission.

George M. Shaw, M.D., Ph.D., professor in the UAB departments of Medicine and Microbiology and senior author on the report, said the research sheds new light on potential vulnerabilities in the virus at a time when science, medicine and society are still reeling from the failure of a major HIV vaccine clinical trial.

“We can now identify unambiguously those viruses that are responsible for sexual transmission of HIV-1. For the first time we can see clearly the face of the enemy,” said Shaw, a project leader with the Center for HIV/AIDS Vaccine Immunology. The center is a National Institutes of Health-sponsored consortium of researchers at UAB, Harvard Medical School in Boston, Oxford University in England, the University of North Carolina in Chapel Hill and Duke University in Durham, N.C.

The new HIV-1 findings are published online in the Proceedings of the National Academy of Sciences.

The new study was performed by sequencing many copies of the HIV envelope gene present in the viruses taken from 102 recently infected patients. The envelope gene encodes for a protein called Env that forms part of the outer covering of the virus, and is responsible for its infectiousness.

The researchers then used sophisticated mathematical models of HIV replication and genetic change to identify the virus or viruses responsible for transmission. In 80 percent of the newly infected patients, a single virus caused transmission, though each virus was different in each patient. In the other 20 percent of patients, two to five unique viruses caused transmission.

“Previously, researchers employed inexact methodologies that prevented precise identification of the virus that initiated infection,” said Brandon Keele, Ph.D., an instructor in UAB’s Department of Medicine and lead study investigator. “Our findings allow us to identify not only the transmitted virus, but also viruses that evolve from it.”

The UAB team said their work would lead to new research on how different HIV genes and proteins work together to make a virus biologically fit for transmission and for growth in the face of mounting immunity.

Statistics show that while the worldwide percentage of people infected with HIV has leveled off, the total number HIV cases is rising. In 2007, 33.2 million people were estimated to be living with HIV, 2.5 million people became newly infected and 2.1 million people died from AIDS, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization.

Source : University of Alabama at Birmingham

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article : The Study finds unique HIV vaccine formula elicits strong immune responses

Today, Advanced BioScience Laboratories, Inc. (ABL) and the University of Massachusetts Medical School (UMMS) report that their unique HIV vaccine formulation was effective in eliciting strong and balanced immune responses in healthy human volunteers. The findings are published in the journal Vaccine (“Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers,” Vaccine online, May 22, 2008) In light of these initial findings, additional assays on volunteers’ samples were done by researchers at the University of Alabama at Birmingham, independently confirming the presence of long lasting and high quality T cell responses against HIV antigens. Results from this confirmatory study are currently available online in the Journal of Virology (April 30, 2008).

In this phase I clinical trial, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), volunteers first received three injections of a DNA vaccine which expresses protective antigens from the HIV virus, followed by two injections of a protein vaccine whose components matched those included in the DNA vaccine. The report in Vaccine is the first scientific article in which a “DNA prime-protein boost” combination vaccination method is tested in humans for HIV vaccine development. Scientists at ABL and UMMS and their collaborators discovered that this combination approach is highly effective in inducing strong antibody and cell-mediated immune responses in human volunteers.

“Given the challenges of developing a vaccine against HIV, scientists have long believed that a final, effective HIV vaccine will require the induction of balanced responses from both arms of human immune system. Our results demonstrate that it is feasible to use this combination approach to achieve this objective,” said Phillip Markham, PhD, of ABL, the Principal Investigator (PI) on this vaccine development effort, performed under contract to the NIAID.

One unique design underlying this combination HIV vaccine formulation is the use of a “cocktail” of five different envelope (Env) proteins collected from HIV viruses circulating in different parts of the world. Env is a key protective antigen and the goal was to elicit broad antibody responses against a wide range of HIV viruses in order to counter the issue of frequent HIV mutations. Indeed, the high titer antibodies found in volunteers’ sera were able to recognize each of a very diverse group of Env antigens that were included in this study. More significantly, the majority of volunteers developed positive neutralizing antibodies against a good portion of the five HIV subtypes included in the assay.

Shan Lu, MD, PhD, professor of medicine and biochemistry & molecular pharmacology at the University of Massachusetts Medical School and the co- Principal Investigator (co-PI) of the vaccine development program, describes the finding of neutralizing antibodies in this study as “a major step forward.”

“Previously, we didn’t know where to start. The neutralizing antibody titers in our study are still relatively low, but, these results are promising and open the door for future efforts to optimize HIV vaccine formulations in order to achieve a protective HIV vaccine,” said Dr. Lu.

The dominant approaches in the current HIV vaccine field rely on viral vector-based delivery systems, an approach that produced disappointing results in a recent efficacy trial. Drs. Markham and Lu believe their HIV vaccine strategy will offer an alternative approach to focus on the induction of protective antibodies for HIV vaccine development, while maintaining strong cell-mediated immune responses. In addition to NIH, the International AIDS Vaccine Initiative (IAVI) also provided funding support to part of the study. Researchers from Duke University Medical School also participated, as did Dr. Paul Goepfert at the University of Alabama-Birmingham.

Source : University of Massachusetts Medical School

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article : Failed HIV drug gets second chance with addition of gold nanoparticles

Researchers at North Carolina State University have discovered that adding tiny bits of gold to a failed HIV drug rekindle the drug’s ability to stop the virus from invading the body’s immune system.

The addition of gold nanoparticles to a modified version of a drug designed in the 1990s to combat HIV – but discarded due to its harmful side effects – creates a compound that prevents the virus from gaining a cellular foothold, say Dr. Christian Melander, assistant professor of chemistry at NC State, and doctoral student T. Eric Ballard.

Their findings appear online in the Journal of the American Chemical Society.

The drug, a compound known as TAK-779, was originally found to bind to a specific location on human T-cells, which blocks the HIV virus’ entry to the body’s immune system. Unfortunately, the portion of the drug’s molecule that made binding possible had unpleasant side effects. When that portion of the molecule – an ammonium salt – was removed, the drug lost its binding ability.

That’s when the researchers turned to gold as the answer. The element is non-reactive in the human body, and would be the perfect “scaffold” to attach molecules of the drug to in the absence of the ammonium salt, holding the drug molecules together and concentrating their effect.

“The idea is that by attaching these individual molecules of the drug with a weak binding ability to the gold nanoparticle, you can magnify their ability to bind,” Melander says.

The researchers’ theory proved correct. They started with a modified version of TAK-779, which didn’t include the harmful ammonium salt. After testing, they found that attaching 12 molecules of the modified drug (SDC-1721) to one nanoparticle of gold restored the drug’s ability to prevent HIV infection in primary cultured patient cells. When only one molecule of the drug was attached to the gold nanoparticle, the compound was unable to prevent HIV infection, indicating that the multivalency of the drug was important for its activity.

“We’ve discovered a non-harmful way to improve the strength and efficacy of an important drug,” Melander says. “There’s no reason to think that this same process can’t be used with similar effect on other existing drugs.”

Source : North Carolina State University

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article : Scientists image a single HIV particle being born

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.”

Source : Rockefeller University

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article : Protein that provides innate defense against HIV could lead to new treatments

Scientists have known that most human cells contain a factor that regulates the release of virus particles, but until now they have been uncertain about the factor's identity. Now a research team from Emory University School of Medicine, Vanderbilt University School of Medicine, and Mayo Medical School has identified CAML (calcium-modulating cyclophilin ligand) as the cellular protein that inhibits the release of HIV particles.

CAML works by inhibiting a very late step in the virus lifecycle, leading to the retention of HIV particles on the membrane of the cell. The virus has developed a means of counteracting CAML, through the action of the viral Vpu protein. When Vpu is absent, HIV particles don't detach from the plasma membrane and instead accumulate by a protein tether at the cell surface.

When the research team depleted CAML in human cells in the laboratory, they found that Vpu was no longer required for the efficient exit of HIV-1 particles from the cell. When they expressed CAML in cell types that normally allow particles to exit freely, the particles remained attached to the cell surface.

"This research is important because it identifies CAML as an innate defense mechanism against HIV," says senior author Paul Spearman, professor of pediatrics (infectious diseases) at Emory University School of Medicine. "We are continuing to work on the mechanism that Vpu uses to counteract CAML and on defining exactly how CAML leads to virus particle retention on the infected cell membrane. We hope this will lead us to new treatments."

Source : Emory University

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article : Trial is first to see if HIV prevention gels are safe for pregnant women, their babies

Clinical trials hoping to identify a vaginal microbicide that is both safe and effective against HIV have all but skirted questions befitting the evaluation of an approach intended primarily for sexually active women of childbearing age: What if a woman becomes pregnant while using a product? Can exposure to a product, especially early in pregnancy, pose a risk to the developing fetus? Does pregnancy affect how a particular microbicide is supposed to work?

Researchers from the Microbicide Trials Network (MTN) and the University of Pittsburgh will begin addressing these and other questions in the first clinical trial of a candidate vaginal microbicide in pregnant women. The National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both components of the U.S. National Institutes of Health, are funding the study.

Women, who represent nearly half of the 33.2 million people living with HIV, are more than twice as likely as men to acquire HIV through sex. Between 70 and 90 percent of all HIV infections in women are acquired during heterosexual intercourse. In the face of these staggering statistics, much research is focusing on the promise of microbicides, products designed to prevent the sexual transmission of HIV when applied topically on the inside of the vagina or rectum.

The trial, known as MTN-002, will enroll 16 healthy HIV-negative women who are scheduled for caesarean delivery at Magee-Womens Hospital of the University of Pittsburgh Medical Center. The women will have a single dose of tenofovir topical gel applied inside the vagina about two hours before giving birth. Tenofovir gel incorporates an antiretroviral drug normally used to treat people with HIV and is among a newer class of candidate microbicides that differ from early types because it has specific activity against HIV.Researchers hope to understand the extent that pregnancy affects how the body absorbs the active drug in the gel and whether the drug can be transferred to the fetus.

"The study of drugs during pregnancy continues to be one of the most neglected areas of biomedical research. As for microbicides, when the very population at risk for HIV is the same population of women most likely to become pregnant, we have a clinical and ethical obligation to pursue studies involving the use and safety of microbicides in pregnancy," said Richard Beigi, M.D., M.Sc., an assistant professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, who is leading the MTN study.

Women in clinical trials of microbicides are typically between the ages of 18 and 40 and required to use effective methods of contraception, in addition to male condoms, for a study's duration. Still, pregnancies are not uncommon, occurring in at least 5 to 10 percent of participants. Because the risks to both women and their babies are not known, women who are found to be pregnant are told to stop using the study product immediately.

"Absent any data, the wisest course of action has been the one we have adopted. But asking women to stop a product is not an approach that would be feasible in a real-world setting, and surely, in the short term, we would do better to have data with which we could inform women in clinical trials," added Dr. Beigi. Dr. Beigi will also lead an MTN registry of women who become pregnant while participating in an HIV prevention trial of either a microbicide or an oral antiretroviral drug, an approach known as pre-exposure prophylaxis, or PrEP; and will include women who have participated in trials like MTN-002. The registry also will help determine the effects, if any, that early exposure to these products may have on fetal and/or neonatal development.

Indeed, a recent Institute of Medicine report on the methodological challenges in HIV prevention trials included among its key recommendations the need to evaluate the potential effects products may have on pregnant women and their fetuses. One argument for such studies is that if a microbicide were to become widely available, pregnant women will be among those using the product. Evaluating safety in this population before any product is marketed is important to ensure that microbicides are used by as many women as can safely benefit. Moreover, studies could also indicate if using microbicides during pregnancy – a time when women may be at even greater risk for acquiring HIV through sexual intercourse – could also help prevent mother-to-child HIV transmission.

Researchers must first understand what happens in pregnancy, when changes in the mother, placenta and the fetus can alter absorption, distribution and elimination of drugs. In MTN-002, researchers will look to see if and how much of the gel's active drug is in the woman's blood and uterus; the placenta and umbilical cord blood; and the amniotic fluid surrounding the baby. Because study gel is being given as one dose right before delivery, just trace amounts of tenofovir, if any, are expected to pass into the bloodstream. Researchers are not sure if the drug goes into the placenta, the amniotic fluid or the baby's blood, which are some of the questions the study seeks to answer.

The active ingredient in tenofovir gel belongs to a class of anti-retroviral (ARV) drugs called nucleotide reverse transcriptase inhibitors. In its pill form, tenofovir is a mainstay of one of the most widely used regimens for treating HIV, and it is increasingly being used during pregnancy. It is also being studied in HIV-infected women late in pregnancy for its potential to prevent mother-to-child transmission of HIV. The topical gel form of tenofovir is an approach being evaluated as a preventive against sexual transmission of HIV. Trials have found it is safe to use by HIV-negative women, but no studies of the gel have been conducted in pregnant women. MTN-002 will include several measures to ensure the safety of the women and their newborns, and it will make use of the resources and expertise of the University of Pittsburgh Obstetric-Fetal Pharmacology Research Unit (OPRU), one of four OPRU sites funded by the NICHD to study the use of pharmacologic agents during pregnancy.

Depending on what is learned in MTN-002, the research team may plan larger trials that will assess repeated tenofovir gel use over longer periods during pregnancy. Demonstrating the safety during pregnancy could potentially allow women who become pregnant during effectiveness trials to remain in the study and continue using the product, say the researchers.

Concurrent with MTN-002, MTN will launch a series of other trials evaluating the safety of and adherence to using tenofovir gel as well as looking at its effectiveness for preventing HIV in nonpregnant women. MTN-001will be the first study directly comparing oral and vaginal gel preparations of tenofovir – looking at differences in drug absorption (systemically and locally) and adherence and acceptability of each approach separately and in combination. The VOICE Study (Vaginal and Oral Interventions to Control the Epidemic) will be the first effectiveness trial evaluating two promising HIV prevention approaches in the same study: tenofovir gel and PrEP, an HIV prevention approach that involves daily use of oral ARVs.

Both oral and topical formulations of tenofovir were developed by Gilead Sciences, Inc., of Foster City, California, which assigned a royalty-free license for the topical gel to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, of Arlington, Virginia, in December 2006. CONRAD is supplying both the gel and gel applicators for MTN-002.

Other microbicide products have been or are currently being tested in clinical trials, although none is yet approved or available for use by women.

Source : University of Pittsburgh

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article : How Know the antiretroviral therapy as HIV prevention strategy

The widespread use of highly active antiretroviral therapy may reduce the incidence of HIV in individuals and populations but has been overlooked by public health as a prevention strategy, write Dr. Julio Montaner and colleagues in CMAJ.

Despite advances in HIV treatment such as topical microbicides, pre- and post-exposure treatment and male circumcision, HIV infections continue to increase worldwide. Dr. Montaner and co-authors argue that "expanded access to highly active antiretroviral therapy for patients with a medical indication will reduce AIDS-related illness and deaths and may reduce HIV incidence."

"At the population level, access to highly active antiretroviral therapy has been temporally associated with substantial reductions in HIV incidence. For example, population-based research in Taiwan found a 53% reduction in new positive HIV test results after the introduction of free access to highly active antiretroviral therapy."

The use of "treatment as an aid to prevention" has been used in public health disease management, with diseases such as tuberculosis and genital herpes. "However, public health policy-makers and program managers have been reluctant to accept this strategy as viable for preventing the growth of the HIV/AIDS epidemic," write the authors.

"Treatment as an aid to prevention should be explored in diverse settings, including in developed and developing countries….Evidence derived from these research efforts will decrease AIDS-related morbidity and mortality and inform policy-makers about the role of treatment as an aid to prevention."

Source : Canadian Medical Association Journal

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article : Infant formula blocks HIV transmission via breastfeeding

Acquired Immune Deficiency Syndrome (AIDS) is a global epidemic threatening the lives of millions of people. Because there is no known cure, prevention of the transmission of the virus that causes AIDS, the Human Immunodeficiency Virus (HIV), is critical for controlling the disease. The transmitting routes of HIV include breastfeeding, which passes the virus from mothers to infants. This is a major problem in many areas of Africa, where HIV-positive mothers have no alternative to breastfeeding. So far, no practical and effective methods are available to prevent HIV transmission by this route.

A team of researchers from Lavax (Palatine, Ill.) and the University of Illinois at Chicago, reporting today during the 86th General Session of the International Association for Dental Research (IADR), is developing a new technology that prevents the infection of HIV by breastfeeding. They have isolated a special strain of probiotic lactobacilli from the human mouth. It belongs to the same species as those found in dairy foods, such as yogurt and kefir. This strain captures the HIV virus by binding to its outer 'envelope'. Because it grows and reproduces itself in milk, once an infant is inoculated with the Lactobacillus, the protection may last until the infant is weaned. This technology offers an easily administered alternative to HIV vaccines, which are currently unavailable. However, the hot climate and the lack of refrigeration in Africa pose a great challenge for the shelf life of lactobacilli. The aim of this study was to develop a lasting formula of lactobacilli for infants to be used as prevention against the transmission of HIV through breastfeeding.

Currently, the best bio-protecting agents for lactobacilli are sucrose and trehalose. These sugars preserve freeze-dried lactobacilli well at 4°C and 20°C. However, at a warmer temperature (33°C), after 4 weeks of storage, all Lactobacillus cells protected with sucrose or trehalose die. By screening a variety of food ingredients for a better protective agent, the investigators have identified a new alternative. This new agent kept the HIV-capturing Lactobacillus strain viable for more than 12 weeks at 33°C. Their analysis showed that, after 12 weeks, the Lactobacillus in the infant formula was as good as fresh Lactobacillus in capturing HIV and blocking the HIV infection of cultured mammalian cells.

In summary, scientists have developed a new preservation method that can maintain HIV-capturing lactobacilli in a hot climate without refrigeration. This method will facilitate the development of a safe and effective prophylactic formula to protect infants from HIV in mother's milk.

Source : International & American Association for Dental Research

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article : How viral complementation allows HIV-1 replication without integration, NYU Dental research shows

Weak HIV viruses piggyback onto stronger ones, raising the possibility that the human body may harbor many more HIV viruses capable of replicating and contributing to the development of AIDS than previously thought, a New York University College of Dentistry AIDS research team has found.

It's widely known that only about one in every 100 HIV viruses can successfully complete the process of integrating its DNA with the DNA of the human cell -- a step that every virus must successfully complete before it can reproduce. But a new study led by Dr. David N. Levy, an Assistant Professor of Basic Science and Craniofacial Biology at the NYU College of Dentistry, has revealed a mechanism that enables some of the other 99 percent of HIV viruses also to replicate and play a potential role in the development of AIDS.

"We've observed a new mode of HIV replication that involves cooperative interaction between viruses," said Dr. Levy, who published his findings today in BioMed Central's open access journal Retrovirology.

According to Dr. Levy, HIV functions as a community, with those viruses that successfully integrate with the DNA in human cells rescuing the viruses that fail to integrate by providing them with the proteins they need to reproduce. In fact, the viruses that were once thought to be lost because they don't integrate may have an advantage over the others because they can skip several steps in their replication cycle and reproduce faster.

"Cooperation between different viruses is yet another one of the many tricks that HIV uses to survive, and raises the possibility that there are more active viruses in the body than was previously thought. Understanding how viruses interact with each other is a key to understanding how HIV evolves and survives the body's immune responses, which we hope could ultimately lead to the development of new ways to treat HIV infection."

Source : New York University

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article : More biology articles in the 'AIDS & HIV' category

n battle with an epidemic that has outpaced nearly all efforts to contain it, researchers are turning to strategies centered on the same antiretroviral (ARV) drugs that have been used successfully to treat HIV in hopes they will be as effective a stronghold for preventing the virus. For women, who make up nearly half of the 33 million people living with HIV/AIDS worldwide, the ARV tenofovir has particular promise because it can be formulated as either an oral tablet or a vaginal gel to be used daily. But ARV-based prevention approaches are not without scientific and practical challenges. The Microbicide Trials Network (MTN) is taking aim at among the most pressing of these challenges in the first clinical trial to directly compare the tablet and vaginal gel formulations of tenofovir.

In part because certain cells in the vagina are easy targets for the virus, women are more than twice as likely as their male partners to acquire HIV through sexual intercourse. As such, the clinical study, known as MTN-001, seeks to understand how each formulation of tenofovir works in these infection-prone cells, information that will help researchers determine the optimal doses needed to achieve drug concentrations most likely to prevent HIV in women.

MTN-001 also looks to understand the factors that influence women's preferences for one daily approach over another, because not even the best approach will be effective if women don't use it.

MTN-001 is a Phase II study designed to evaluate women's adherence to and acceptance of three daily regimens of tenofovir – tenofovir gel, tenofovir disoproxil fumarate tablets and the two together – and the pharmacokinetics, or how the drug is absorbed by and distributed in the body over time, of each regimen. The study will enroll 144 sexually active HIV-negative women who will follow all three regimens, each for six weeks with one week between when no study product is used. In the United States, Case Western Reserve University in Cleveland and the University of Pittsburgh are now beginning to screen potential participants.

Additional sites, including in South Africa and Uganda, will also be participating in the study, which is funded by the National Institute of Allergy and Infectious Diseases, a component of the U.S. National Institutes of Health. Researchers expect to complete the study in 2009.

"Being able to capture in one study, and in all women, information about adherence, acceptability, and pharmacokinetics will help us answer critical questions about the three regimens more efficiently and with greater confidence than we could in separate studies. We will be able to more clearly discern the differences between each formulation, including at the cellular level, and get a more accurate reading on women's preferences and adherence patterns," said Craig W. Hendrix, M.D., associate professor of medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine in Baltimore, Maryland, who, as MTN-001 protocol chair, is leading the multi-site study.

In its tablet form, tenofovir disoproxil fumarate, known by the brand name Viread, is a mainstay of one of the most widely used regimens for treating HIV. The active ingredient in tenofovir belongs to a class of ARVs called nucleotide reverse transcriptase inhibitors (NRTIs), which act against HIV by targeting a key enzyme the virus needs to make a copy of its genetic material – an essential step for the virus to multiply and infect other cells. Tenofovir is being evaluated in clinical trials to determine if this first-line treatment can also prevent HIV when used every day by people who are HIV-negative, an approach known as pre-exposure prophylaxis, or PrEP. As a vaginal gel, tenofovir is among a newer class of candidate microbicides with specific activity against HIV. Microbicides are substances designed to prevent or reduce the sexual transmission of HIV when applied topically on the inside of the vagina or rectum.

In MTN-001, researchers will assess women's adherence to each of the three tenofovir regimens through structured interviews and questionnaires. Questions will focus on their overall experience using the product regimen, asking how sexual activity may have changed, how well the regimen was adhered to and why the product was not always used— did they forget, dislike using the product or give the tablet or gel to other people? A small number of participants from each site also will take part in in-depth interviews at the end of the 21-week study so researchers can collect more detailed information, including about women's adherence to and preferences between oral and vaginal formulations and between single and dual-use regimens.

Researchers will conduct pharmacokinetic studies of blood plasma (the liquid component of blood), white blood cells, vaginal tissue and cells taken from inside the vagina. For instance, at each mid-study period, participants will provide a small amount of blood that will be used to determine how much tenofovir is circulating in the blood. At sites with laboratory capacity, blood will also be used to determine if tenofovir is present inside blood cells and, if so, whether the drug is in its active or inactive state. Such studies are important because tenofovir is not effective against HIV unless it has been activated by the addition of two molecules called phosphates, much like a lamp can only be turned on if it has both a light bulb and switch.

At the end of each study period, participants will follow their assigned regimen at the clinic, and similar tests will be conducted of both blood and vaginal fluid. The 48 women enrolled at the two U.S. sites will be involved in more intensive assessments of each approach whereby researchers will look at blood and tissue samples at different periods of time after taking the drug.

"Information gathered in these intensive studies, plus information from other trials, will help us build a picture showing the relationship between plasma blood levels of drug and the amount of activated drug inside the HIV target cells of vaginal tissue. It may be possible to determine the concentration of drug inside vaginal cells with a simple blood test, and then extrapolate the required drug dose to reach the target concentration for preventing HIV," explained Dr. Hendrix.

MTN-001 is part of a portfolio of trials evaluating the oral and gel forms of tenofovir. Recently, MTN researchers launched the first trial in pregnant women, seeking to understand the extent that pregnancy affects how the body absorbs the active drug in the gel and whether the drug can be transferred to the fetus. The VOICE Study (Vaginal and Oral Interventions to Control the Epidemic), a trial involving 4,300 women that is expected to begin early 2009, will be the first effectiveness trial evaluating in the same study both a microbicide (tenofovir gel) and PrEP (oral tenofovir and oral Truvada, a combination of tenofovir disoproxil fumarate and another antiretroviral agent called emtricitabine).

Source : Microbicide Trials Network

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