amfAR, The Foundation for AIDS Research

July 2008: New amfAR Grants Look to Optimize Current HIV Treatment and Strive for a Cure

July 16, 2008 – amfAR, The Foundation for AIDS Research, will award more than $1.4 million in grants to fund 12 new research projects whose findings may fundamentally change the way HIV/AIDS is treated, Dr. Rowena Johnston, amfAR’s vice president of research, announced today.

The 12 new projects will address factors, in particular beliefs and attitudes surrounding HIV, which negatively impact the effectiveness of available treatments. At the same time, amfAR is seeking a longer-term solution to difficulties associated with lifelong treatment by supporting projects aimed at eradicating HIV infection.

“Advances made in HIV treatment have arguably been the great success story of AIDS research, and yet two limitations continue to dog our efforts,” Dr. Johnston said. “One is that not all people, even in the United States, benefit equally from these treatment advances. And second, there is still no cure for HIV.”

The social/behavioral projects being funded by amfAR focus on the role that certain beliefs, especially those pertaining to the origin of HIV or the availability of alternative treatment or prevention interventions, play in a person’s decision to follow the advice of healthcare professionals. Through in-depth interviews, Dr. Scott Rhodes of Wake Forest University Health Sciences, will attempt to identify the beliefs and other factors that influence Latinos’ decision to access science-based HIV treatment and prevention services.

Few studies have examined the Latino population, which is facing a rapidly rising infection rate. In 2006, Latinos accounted for 18 percent of new HIV diagnoses in the United States, though they only make up about 13 percent of the population, according to the U.S. Centers for Disease Control.

Other projects include an examination of beliefs and attitudes in South Africa surrounding male circumcision, recently shown to reduce the risk of acquiring HIV by around 50 percent, and a case study that will use the wealth of records in the V.A. system to assess the impact that misinformation has on treatment adherence in those receiving treatment for HIV.

Several biomedical researchers are testing treatment strategies that might lead to the eradication of HIV. Dr. David Margolis of UNC-Chapel Hill is testing several compounds that can switch on genes to start making proteins. He is testing whether these compounds can be used to turn on the replication of latent, or non-reproducing, virus. Once activated, the virus would then be susceptible to, and possibly even eliminated by, existing antiretroviral therapy regimens.

“It’s time to come up with fresh approaches to old problems,” Dr. Johnston said. “Some of the issues facing us in HIV are similar to those plaguing other diseases. How do we make sure every person has the same access to the advances of modern medicine? How do we cure viral diseases? Once we crack the code, we unlock the potential for better health for all.”

amfAR has also issued three new requests for proposals for biomedical research, social/behavioral studies, and its Krim Fellowship program for young scientists. For more information, click here.

The recipients of this $1.4 million round of funding and their projects are:

Biomedical Grants

Zandrea Ambrose, Ph.D.
University of Pittsburgh, Pittsburgh, PA

In vivo virus persistence during suppressive therapy in the RT-SHIV model: While it is clear that current antiretroviral therapy (HAART) regimens do not eliminate HIV infection, less well understood are the locations of reservoirs in which the virus hides beyond the reach of HAART. Dr. Ambrose will conduct studies in monkeys infected with a simian version of HIV that responds to HAART. She will describe the location of the virus in the body when the infection is in the early stages of treatment, the later stages, and in untreated infection. These studies will help to determine how and where reservoirs of untreatable HIV are laid down early during infection and may point to strategies to prevent or eliminate these reservoirs.

Cristian Apetrei, M.D., Ph.D.
Tulane National Primate Research Center, Covington, LA

Animal model for controlled SIV infection: When Indian rhesus macaques are infected with SIV (a monkey analog of HIV) from African green monkeys, they show high levels of viral replication and severe depletion of CD4 cells, just as in humans infected with HIV. Over the long term, however, and unlike most infected humans, these macaques bring their infection under control without antiretroviral therapy. Dr. Apetrei plans to study how these animals are ultimately able to control the extent to which the virus reproduces and how the immune system recovers from the initial damage. His work will provide clues for the design of therapeutic strategies to bring about similarly beneficial results in human patients.

Paul Denton, Ph.D./Mentor: J. Victor Garcia-Martinez, Ph.D.
UT Southwestern Medical Center, Dallas, TX

In vivo modeling of HIV persistence and its eradication: Taking advantage of a mouse model of HIV infection recently developed in the Garcia-Martinez laboratory, Dr. Denton plans to track the decline in HIV during antiretroviral therapy (HAART), where the virus establishes itself in anatomical reservoirs beyond the reach of therapy, the nature of viral rebound when HAART is removed, and whether pharmacological interventions can prevent the establishment of, or eliminate, the reservoirs that represent a barrier to a cure. These studies will confirm whether this mouse model will be useful in designing interventions to cure HIV infection in humans.

Vojo Deretic, Ph.D.
University of New Mexico HSC, Albuquerque, NM

Autophagy and intracellular HIV in macrophages: HIV subverts numerous healthy cell processes to replicate itself and spread infection throughout an infected person. One such process, known as autophagy, is a mechanism normally used by dendritic cells (DCs) and macrophages of the immune system to digest and destroy infectious particles. HIV instead uses this machinery to hitch a ride through the body to find vulnerable cells to infect, all the while beyond the reach of antiretroviral therapy (HAART). Dr. Deretic plans to explore ways to re-activate the HIV-destroying potential of DCs and macrophages and thus remove one source of viral persistence during HAART.

David Margolis, M.D.
The University of North Carolina at Chapel Hill, Chapel Hill, NC

HDAC inhibition and chromatin remodeling to disrupt proviral latency: Under some circumstances, HIV integrates itself into an infected cell’s DNA but does not switch on its own replication. This latent infection is impervious to the effects of antiretroviral therapy (HAART). One class of compounds, histone deacetylase (HDAC) inhibitors, has been found to switch on the replication of latent virus, and in the presence of HAART it can deplete the amount of latent virus in an infected person. Dr. Margolis will investigate the effectiveness of different HDAC inhibitors and characterize the different kinds of HDACs that must be inhibited to achieve optimal depletion of latent HIV, thus bringing researchers closer to a cure.

Sarah Palmer, Ph.D.
Swedish Institute for Infectious Disease Control, Karolinska Institute, Solna, Sweden

Treatment intensification: Effects on persistent viremia: Recent additions to the arsenal of antiretroviral therapy (HAART) will allow Dr. Palmer to investigate how virus replication rebounds to high levels after treatment is removed. She will analyze the genetic sequences of viruses in patients before and after new therapeutic agents (raltegravir or maraviroc) are added to intensify their standard treatment regimen. These studies will shed light on the sources from which virus levels rebound, specifically from sanctuary sites in the body where HAART does not penetrate optimally, from cells that persistently produce low levels of virus despite HAART, or from truly latently infected cells that sporadically produce virus.

Rafick-Pierre Sekaly, Ph.D.
Université de Montréal, Montreal, Canada

IL-7 and antigen driven proliferation generate distinct HIV reservoirs: HIV can persist in a subset of CD4 T cells beyond the reach of the immune system or antiretroviral therapy, but the mechanisms that allow these infected cells to persist are not clearly delineated. Dr. Sekaly will compare infected cells from patients in clinical trials who have received injections of vaccine candidates versus injections of an immune stimulating hormone (the cytokine IL-7). These studies will probe the extent to which the maintenance of latently infected cells is due either to an active turnover of infected cells as they are killed by the immune system and reproduce themselves, or to the normal process whereby the immune system maintains appropriate numbers of cells.

Celsa A. Spina, Ph.D.
University of California San Diego, La Jolla, CA

Quantification of HIV provirus: Integration and replication competence: Efforts to eradicate HIV from infected individuals are complicated by the extremely low rate at which vulnerable cells are ultimately latently versus actively infected. Researchers testing new strategies to reduce or eliminate latently infected cells currently experience difficulty measuring changes in the numbers of those cells because of the limits of current technology. Dr. Spina plans to address this issue by making improvements to one current cell-counting method. She will also devise new methods to both register changes in numbers of latently infected cells as well as characterize whether virus found in those cells is capable of reproducing.

Social/behavioral Grants

Joanne Mantell, Ph.D.
Research Foundation for Mental Hygiene, Inc., New York, NY

HIV prevention efficacy beliefs about male circumcision in South Africa: Three randomized controlled trials conducted in South Africa, Kenya and Uganda demonstrated that male circumcision (MC) reduced the risk of HIV among adult heterosexual men by as much as 61%. However, MC provides only partial protection against HIV infection for heterosexual men, and may not protect women. Misunderstandings about the partial effectiveness of MC could generate significant mistrust and distortion of existing scientific evidence about MC as the technology is “scaled up”, especially in a setting such as South Africa, where mainstream causes of AIDS have been challenged. Information from this study will be used to guide program planning for the widespread availability of MC.

Kristin Mattocks, Ph.D./Mentor: Paul Cleary, Ph.D.
Yale University, West Haven, CT

What they're not telling me: Veterans, trust, and HIV care in the VA: Previous research has suggested that lack of trust in evidence-based medicine is an important barrier to the use of health services among those receiving care for HIV. Furthermore, some research has suggested that endorsement of the belief that HIV was created to cause harm may lead to reduced condom use among some populations. To investigate the relationship between these kind of beliefs, mistrust, and self-care behaviors such as medication adherence, Dr. Mattocks will conduct analyses of data collected under the auspices of the Veterans Aging Cohort Study. Understanding the role of mistrust in this population can lead to a better understanding of patients’ initiation of and adherence to antiretroviral therapy.

Scott Rhodes, Ph.D.
Wake Forest University Health Sciences, Winston-Salem, NC

Trust and mistrust of evidence-based medicine among Latinos with HIV: Despite advances in medical care and treatment, Latinos with HIV in the US have higher mortality rates than whites. Mistrust of evidence-based medicine, including providers and treatment regimens, may play a role in Latinos with and at increased risk for HIV deciding not to seek needed care and/or follow medical and healthcare recommendations. Dr. Rhodes will conduct individual in-depth interviews to identify salient beliefs and other factors that may influence trust and mistrust of evidence-based medicine. Study findings will help shape new intervention approaches and strategies to reduce the disproportionate HIV/AIDS disease burden and disproportionate mortality among Latinos.

Waimer Tun, Ph.D.
The Population Council, New York, NY

HIV conspiracy beliefs and misinformation among South African MSM: South Africans have long been the recipients of mixed messages from political leaders, for example, about the origins, treatment and prevention of HIV. Dr. Tun will investigate the extent of HIV misinformation and mistrust in medical providers and institutions among men who have sex with men in South Africa, what factors may influence HIV misinformation and mistrust, and the impact HIV misinformation and mistrust have on condom use, HIV testing, accessing HIV prevention, care and treatment services, and willingness to participate in future HIV prevention/treatment trials. Results of this study will be used to identify effective strategies to disseminate accurate health information.