June 2006: Grants and Fellowships Announced: amfAR Funds Studies Aimed at Viral Eradication

June 27, 2006 - amfAR, The Foundation for AIDS Research, today announced 12 grants and fellowships to investigate the potential of eradicating HIV from the body. These new awards, totaling nearly $1.5 million, represent amfAR’s commitment to funding scientific studies that may reveal how to eliminate the virus altogether. Many consider research focused on viral reservoirs, latent virus and acute HIV infection to be the first steps toward an elusive cure for HIV infection.

“In the past, scientists have regarded talk of ‘AIDS cures’ with suspicion,” said Dr. Rowena Johnston, who directs amfAR’s research program. “A quarter-century of dashed hopes make even the most optimistic scientific minds reluctant to imagine a body free of HIV. The grantees and fellows we have selected recognize the complexity of HIV eradication. But their work engages the virus in radical new ways which may realize our hope that we will someday find a cure for AIDS.”

The research that led to highly active antiretroviral therapy (HAART) in 1996 remains one of the key scientific success stories in the 25-year-old epidemic. But even though HAART prolongs life by suppressing viral reproduction, reservoirs of latent virus remain throughout the body. Because latent virus hides beyond the reach of HAART, it creates an impediment to eliminating HIV from the body altogether.

Dr. Paul Bieniasz will receive one of amfAR’s newly announced grants. Bieniasz, whose laboratory is at the Aaron Diamond AIDS Research Center in New York, will use genetic engineering to create viral latency in the test tube. He will then apply an innovative technique to generate millions of new peptides that can be evaluated for their ability to reduce or eliminate latency. Such peptides may ultimately form the basis of new treatments to eradicate HIV in patients.

"amfAR's decision to pursue viral eradication is a bold one," said Dr. Bieniasz. “Disappointments in AIDS research have made many funders view tackling HIV infection using existing treatment paradigms as the most productive use of limited resources. amfAR, which has
supported AIDS research for 20 years, understands that scientific risk-taking can yield extraordinary results."

Among the eight grants and four fellowships are several that, like Dr. Bieniasz’s project, will explore potential methods of flushing latent virus from reservoirs so it can interact with drugs. Dr. Jean-Pierre Routy of McGill University in Montreal will test the ability of a drug commonly used to treat epilepsy to target latent virus in different types of immune cells. Dr. Steven Deeks of the University of California, San Francisco will study HIV-infected people whose immune systems are able to control the virus without the use of antiretroviral therapy. These “elite controllers” may hold a key to understanding genetic alterations that render some virus unable to reproduce.

amfAR, which has funded biomedical research on HIV and AIDS since it was founded, is credited with many important developments that have radically changed HIV/AIDS treatment, including early studies critical to the development of the fusion inhibitor Fuzeon, currently used to save the lives of people resistant to all other HIV treatments. amfAR has also supported pioneering research that ultimately led to the use of AZT to block mother-to-infant HIV transmission, resulting in its near elimination in the industrialized world.

“In terms of what is considered achievable, the climate is beginning to change in AIDS research,” said Dr. Johnston. “While it is important that scientists continue to pursue new ways to halt viral replication and devise new therapies to treat infected people, the need to actively investigate how to rid the body of HIV once and for all has finally been introduced as a reasonable goal for the epidemic’s second quarter-century.”

amfAR, The Foundation for AIDS Research, is one of the world’s leading nonprofit organizations dedicated to the support of AIDS research, HIV prevention, treatment education, and the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested nearly $250 million in its programs and has awarded grants to more than 2,000 research teams worldwide.

Grants

Paul Bieniasz, Ph.D.
Aaron Diamond AIDS Research Center, New York, NY
$120,000

Genetic screens for inhibitors of HIV latency: One potential strategy to eliminate viral reservoirs in HIV-infected people is to flush the virus out of its latent state so that it can be targeted by antiretroviral therapy and/or the immune system. Dr. Bieniasz will genetically engineer cells in the test tube to harbor latent HIV. He will then use an innovative combinatorial library technique to generate millions of new peptides and test their ability to specifically flush the virus out of latency. Such peptides could be used as models to generate compounds that, in conjunction with antiretroviral therapy, could bring researchers closer to being able to eradicate HIV infection.

Steven Deeks, M.D.
University of California, San Francisco, San Francisco, CA
$120,000

HIV controllers: a potential model for HIV eradication: A very small proportion of all people infected with HIV can achieve durable control of the virus without using antiretroviral therapy. Dr. Deeks has identified about 50 people – “elite controllers” – who test HIV-positive and yet whose levels of virus are below the limits of detection using standard laboratory techniques. He will test his hypothesis that these individuals harbor virus that is defective such that it is incapable of reproducing. If this is the case, he will study which genetic alterations in the virus make it replication-incompetent and how those mutations may have arisen. Dr. Deeks’s goal is to determine whether “natural eradication” of HIV is possible.

Sharon Lewin, FRACP, Ph.D.
Monash University, Melbourne, Australia
$120,000

The role of CCR7 ligands and dendritic cells in latent HIV infection: HIV that enters cells but does not replicate exists in a state of latency and cannot be targeted by antiretroviral therapy, thus constituting a major barrier to virus eradication. Dr. Lewin plans to generate a test tube system whereby HIV latency can be studied. While we know that latency can occur in infected people, it is difficult to induce latency in cells taken from the body and grown in the laboratory. Dr. Lewin will probe why this difference exists, thus defining which factors contribute to latency during natural infection. Understanding how latency is established will help scientists devise methods to counteract it.

Binhua Ling, M.D., Ph.D.
Tulane National Primate Research Center, Covington, LA
$120,000

Reservoirs of SIV in long term nonprogressors in rhesus macaques: SIV, a monkey virus closely related to HIV, affects different monkey species in different ways. Dr. Ling is taking advantage of the observation that, as opposed to other species of macaque, about one-third of Chinese rhesus macaques do not progress rapidly to simian AIDS. She will study potential differences in the cell types and tissues involved in viral reservoirs when comparing those that progress rapidly to AIDS to those that do not. Understanding the role played by reservoirs in maintaining and re-seeding infection throughout the body will provide insight for strategies to reduce HIV reservoirs in infected people.

Martin Markowitz, M.D.
Aaron Diamond AIDS Research Center, New York, NY
$120,000

The GI tract may be a reservoir of ongoing viral replication during HAART: HIV kills immune cells in the gastrointestinal tract early in infection, and even after antiretroviral therapy (ART) is initiated, these cells are not replaced. In an effort to understand this persistent defect, Dr. Markowitz will test his hypothesis that even when ART brings virus under control in the blood, there is ongoing HIV replication in the gastrointestinal tract that may be a major source that repopulates the body with virus after drug therapy is withdrawn. His study results from HIV-positive patients will help to guide interventions aimed at preventing the loss, or replenishing of, immune cells in the gastrointestinal tract.

David McDonald, Ph.D.
Case Western Reserve University, Cleveland, OH
$120,000

Role of lymph node dendritic cells in HIV infection: When HIV infection spreads from one cell to another, most cells that become infected actively produce progeny virus, but a small number become latently infected, with low or no production of new viruses. Dr. McDonald plans to study the role of one type of immune cell, known as a dendritic cell, in promoting latent infection of other immune cells. Because latent cells can eventually become activated and begin to produce new viruses, understanding how latency is established will be important in devising therapeutic strategies that could prevent latent reservoirs from replenishing virus levels during the course of HIV infection.

Bapi Pahar, Ph.D.
Tulane National Primate Research Center, Covington, LA
$120,000

Identifying the major tissue reservoirs in SIV/SHIV infected macaques: A small proportion of those infected by HIV can control virus levels indefinitely without the use of antiretroviral therapy. Dr. Pahar will study monkeys infected with a close relative of HIV, called SIV, to determine whether there are differences between those that control virus levels versus those that have high viral load. Specifically, differences in both the location of viral reservoirs and type of cells involved will be compared between the two groups of monkeys. Results from these studies may be used to redirect antiretroviral therapy and AIDS vaccine strategies.

Jean-Pierre Routy, M.D.
McGill University Health Centre, Montreal, Canada
$119,827

Effects of valproic acid therapy on gut mucosal HIV reservoirs: Reducing or eventually eliminating HIV reservoirs is a key goal towards which scientists are striving. One strategy already being tested in a small number of patients involves administering a compound called valproic acid (commonly used to treat epilepsy) in conjunction with antiretroviral therapy. Dr. Routy will extend an existing study of 50 patients on valproic acid to pursue more in-depth analyses of the effects of valproic acid on different types of infected immune cells. Comparisons will be made between cells collected from the blood and gastrointestinal tract, and between cells that have copies of the virus integrated into their DNA and cells with virus outside the DNA.

Fellowships

Beau Ances, M.D., Ph.D./Mentor: Ronald Ellis, M.D., Ph.D.
University of California, San Diego, San Diego, CA
$125,000

Quantitative fMRI of CNS-T ART on HIV brain reservoirs: Mental impairment due to HIV disease can be difficult to treat because many antiretroviral drugs do not penetrate into brain tissues and thus do not target HIV in the brain. Dr. Ances will use quantitative functional magnetic resonance imaging (fMRI) to measure the brain function of HIV-positive patients before and after initiating antiretroviral therapy (ART). fMRI allows brain function – changes in blood flow and oxygen consumption – to be measured non-invasively. He will determine whether ART changes these measures of brain function and whether those changes depend on the degree to which ART penetrates into the brain.

Fedde Groot, Ph.D./Mentor: Quentin Sattentau, Ph.D.
University of Oxford, Oxford, United Kingdom
$124,882

HIV-1 cell-cell spread in viral dissemination and persistence: During early HIV infection, the virus targets and kills cells primarily in the gastrointestinal tract. Dr. Groot plans to establish a test tube system to study how the virus spreads from one infected cell to an uninfected target cell, whether certain types of immune cells are optimally suited to spread the virus, and whether such virus spread can be controlled by experimental drugs or antibodies. The degree of cell loss in the gastrointestinal tract largely determines the course of disease, and Dr. Groot’s findings may guide future efforts to reduce or even prevent this cell loss.

Sara Pagans, Ph.D./Mentor: Melanie Ott, M.D.
The J. David Gladstone Institutes, San Francisco, CA
$125,000

Role of Tat methylation in HIV latency: A major barrier to the eradication of HIV is the tendency for a small amount of virus to remain in a latent state inside cells, during which time antiretroviral therapy cannot target the virus. Dr. Pagans is testing the hypothesis that modifications to the viral protein Tat allow this small fraction of the virus to enter into the latent state rather than to reproduce. Understanding how latency is established will allow scientists to devise treatment methods that could ultimately prove helpful in the quest to eradicate HIV from the body of an infected person.

Nicole Webster, Ph.D./Mentor: Suzanne Crowe, M.D.
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia
$125,000

Macrophage matrix metalloproteinases role in persistence of HIV-1 in CNS: Once HIV infection becomes established in the brain, it can be particularly difficult to treat because not all current medications penetrate well through the blood-brain-barrier. Certain immune cells called monocytes/macrophages control key functions in interactions between other cells in the brain. Dr. Webster will investigate the hypothesis that HIV infection of these cells can disrupt their ability to properly regulate brain cell interactions and may contribute to HIV-associated dementia. The brain can be an important reservoir of HIV, so an improved understanding of its effects in the brain may lead to new strategies to address HIV-associated dementia.