amfAR, The Foundation for AIDS Research announced that it has awarded 12 grants to researchers in the United States and around the world to pursue cure-focused HIV research. The new grants total more than $2.15 million, the largest sum disbursed by amfAR focused on HIV cure research. Read the full press release here.
Ashwin Balagopal, M.D.
Johns Hopkins University, Baltimore, MD
Latent HIV in Kupffer Cells: In order to cure HIV, it will be important to discover all of the cell types in which persistent HIV can reside, beyond the reach of antiretroviral therapy (ART) or the immune system. The types of cells that can be infected by HIV fall into two broad classes – T cells and myeloid cells. Far less is known about the latter, which comprises several different types of cells. Dr. Balagopal is interested in determining the extent to which Kupffer cells, a type of myeloid cell found in the liver, harbors persistent HIV and thus poses a barrier to a cure. Using liver biopsy tissue, they will quantify how much HIV can be found in these cells, how well the virus responds to ART, and whether the HIV in these cells is capable of replicating. This study will provide important information in determining the range of cells that form the persistent reservoir of HIV.
Cheryl Cameron, Ph.D.
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL
Dissecting the Role of the mTOR pathway in CD8 Restriction of HIV Persistence: Dr. Cameron and colleagues will investigate the possibility that mTOR, a protein normally involved in several functions important to a cell’s growth and ability to make proteins, plays a role in determining the size of the HIV reservoir. They are building on the hypothesis that an immune suppressive drug called sirolimus, which blocks the mTOR protein, may have contributed to the reduced reservoir size in HIV patients receiving stem cell transplants to treat their cancer. They have also observed that mTOR levels are lower in elite controllers, patients with smaller than usual reservoir sizes who do not need antiretroviral therapy to keep their HIV under control. Dr. Cameron seeks to confirm the relationship between mTOR and reservoir size, which could lead to a way to treat patients to reduce their reservoir sizes.
Richard D’Aquila, M.D.
Northwestern University, Chicago, IL
Understanding the HIV-APOBEC3G interaction to prevent HIV persistence: Cells have a number of mechanisms to protect themselves from HIV, one of which is APOBEC3G, which causes offspring viruses to have so many mutations that they cannot replicate. Dr. D’Aquila hypothesizes that APOBEC3G is most active at the beginning of an HIV infection, but that over a period of several months its activity drops off, which allows the persistent reservoir of virus to expand. His hypothesis is supported by observations that patients who can control infection without antiretroviral therapy tend to have higher levels of APOBEC3G. He plans to delve deeper into understanding the role of APOBEC3G in determining the size of the reservoir, the results of which may lead to new treatments to reduce reservoir size.
Felipe Garcia, M.D., Ph.D.
Consorci Institut D'Investigacins Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Viral reservoir dynamics after therapeutic vaccination and cART interruption: Using biological samples available to them from a recently concluded clinical trial, Dr. Garcia and colleagues will determine whether an investigational therapeutic vaccine decreased the size of the reservoir in those patients who received the vaccine versus the placebo. The vaccine was able to decrease the amount of virus measurable in the blood after study subjects stopped taking antiretroviral therapy. The investigators hypothesize that this was achieved by boosting the immune system, and they plan to determine whether the boosted immune system also killed some fraction of the HIV reservoir.
Nancy Haigwood, Ph.D.
Oregon Health and Science University, Portland, OR
Reducing Latent Viral Reservoirs in Infant Macaques: One of the great advances in HIV research has been the discovery that treating mothers and infants with antiretroviral therapy can greatly reduce the chances that a newborn will become infected. However, once infection is established the infection – including the establishment of reservoirs, proceeds as usual. Dr. Haigwood and colleagues will test the ability of antibodies to alter the course and/or size of the establishment of the reservoir. They will test in macaques the effects of antibodies found to be effective in controlling HIV in humans. Results will inform our understanding of how and when the reservoir is established, and may indicate new directions for therapy for newborns.
Hiroyu Hatano, M.D.
University of California San Francisco, San Francisco, CA
Determining Viral Reservoir During Hyperacute HIV Infection in PrEP Participants: The HIV reservoir is established very early during HIV infection, but one difficulty in studying its establishment is identifying people in the first few weeks of infection. Dr. Hatano and colleagues plan to recruit subjects from ongoing studies of pre-exposure prophylaxis (PrEP), in which uninfected people take antiretroviral therapy to protect themselves from infection. Because these study subjects are HIV-tested frequently, the researchers believe they will be able to identify subjects in the first couple of weeks of infection. This will allow them to discover which cells HIV infects at various stages during acute infection, and how very early treatment might affect the size or distribution of the reservoir.
Mario Ostrowski, M.D.
University of Toronto, Toronto, Canada
Can therapeutic vaccination reduce viral reservoirs in early cART treated HIV?: Dr. Ostrowski and colleagues will conduct a small pilot clinical trial of a therapeutic vaccine to determine whether it can reduce the size of the reservoir. The vaccine will be tested in subjects who started antiretroviral therapy early in infection, within 6 months of acquiring HIV. The vaccine is intended to induce cellular immunity, one arm of the immune system responsible for killing cells that are infected with the virus. The researchers will measure the size of the reservoir in both the blood and the gut.
Sarah Palmer, Ph.D.
University of Sydney, Sydney, Australia
Genetic analysis of unspliced HIV RNA produced during HDAC inhibitor therapy: One strategy scientists are pursuing to cure HIV is known as “shock and kill”, in which a drug agent is used to “shock” latently infected cells in order to force them to start producing the virus, and the immune system (or some other agent) would kill the infected cells. A clinical trial of one such “shock” agent, belonging to a class of drugs called HDAC inhibitors, was recently conducted in Australia. Those investigators found evidence that some infected cells did indeed start to produce the virus. Dr. Palmer plans to analyze the genetic makeup of the viruses that started to be made, to determine how well the HDAC inhibitor penetrated into different tissues, which cells harbor virus that can be “shocked” with HDAC inhibitors, and which types of cells or tissues the virus came from.
Jonah Sacha, Ph.D.
Oregon Health and Science University, Portland, OR
Role of graft versus host in SIV clearance following stem cell transplantation: The first cure of HIV took place in a man who received a stem cell transplant to treat his leukemia. Subsequently, two HIV-infected patients in Boston who received stem cell transplants to treat their cancers experienced a dramatic reduction in the size of their reservoirs, although the virus eventually rebounded. Dr. Sacha and colleagues want to determine the contribution of graft versus host disease (GVHD) to the reduction in the size of the reservoir in each of these cases. GVHD occurs when the transplanted stem cells reject that transplant host – this may be of benefit in the setting of HIV if the transplant kills the host’s HIV-infected cells. They will test the effect of GVHD on reservoir size using Mauritian cynomolgus macaques, which are highly inbred and thus it will be easy to find donor cells to use. Parsing the contribution of GVHD, versus other elements of the stem cell transplantation procedure, to the reduction in reservoir size will provide clues as to the best approaches to try.
Rafick-Pierre Sékaly, Ph.D.
Vaccine and Gene Therapy Institute Florida, Port St Lucie, FL
Modulating Inflammation for Immune Reconstitution and HIV Eradication: After the Berlin patient was cured of HIV, researchers became very interested in the potential of gene therapy to generate a source of cells to transplant into HIV-positive patients as a potential cure. One company, Sangamo, has used an enzyme called zinc finger nuclease to cut the protein CCR5 out of patients’ T cells in a test tube, thus producing cells similar to those transplanted into the Berlin patient. After transplanting these modified cells back into patients, they have observed varying levels of restoration of the immune system. Dr. Sékaly hypothesizes that the survival of the transplanted cells depends on the level of immune inflammation at the time of transplantation. He will use samples of blood and tissue from the Sangamo studies to test his hypothesis.
James Stivers, Ph.D.
Johns Hopkins University, Baltimore, MD
Persistence and Fate of Invisible U/A Pairs in HIV-1 Proviral DNA: Dr. Stivers and colleagues want to understand the mechanisms whereby viruses can become latent in infected cells. When immune cells are not replicating, they have high levels of a nucleotide called deoxyuridine triphosphate (dUTP). When HIV enters a cell, it must make a DNA copy of itself before it can insert itself into the human cell DNA. In cells with high levels of dUTP, the cell pairs up dUTP with the A nucleotide, to make A/U pairs instead of the expected A/T pairs. If viruses with these DNA errors insert themselves into the human DNA, they cannot replicate, and must wait until the cell becomes activated in order for this error to be corrected. Dr. Stivers and his colleagues hypothesize that viruses with these kinds of errors in their DNA may comprise an important portion of the latent reservoir of HIV, and will search for markers of this “U” in the viral DNA to determine how common it is, where it occurs within the DNA, and how well it can persist. These studies will lead to an increased understanding of the variety of ways in which a virus can become latent.
Blanton Tolbert, Ph.D.
Case Western Reserve University, Cleveland, OH
Host and Viral Control of P-TEFb Activation and HIV Transcription Elongation: Patients who are successfully treated with antiretroviral therapy nevertheless have cells that are infected with HIV that is not actively replicating. To cure HIV, we need to understand how this small proportion of the virus maintains its latent state. While it is known that this latent state is maintained by a combination of factors including the levels of certain key proteins as well as the structure of the DNA that the viruses is integrated into, Dr. Tolbert is interested in understanding more precisely the series of events that lead to the recruitment of P-TEFb to the viral DNA. This recruitment is responsible for the virus’s ability to make copies of its own genetic material, without which it cannot replicate. Leaning all the steps involved in this process might yield clues in the development of a drug to force the virus out of latency.