ARCHE Research Teams and Their Projects
Swedish Institute for Infectious Disease Control and Karolinska Institutet, Solna, Sweden
Sarah Palmer, PhD. – principal investigator
Frederick Hecht, MD. – collaborating investigator
Characterizing and targeting persistent HIV viremia:
Dr. Palmer will work with Dr. Hecht to analyze HIV found in blood and tissue samples of patients who initiated antiretroviral therapy either during acute HIV infection or later. Their goal is to identify which cells produce the virus that is routinely measured in plasma, virus that persists despite very effective antiretroviral therapy. Genetic sequences of plasma viruses will be compared to the sequences of viruses isolated from peripheral blood cells, cells in the gastrointestinal tract, and the bone marrow. This study will help define where the persistent plasma virus is being produced. In addition, because the researchers have access to samples from patients dating from before the initiation of antiretroviral therapy and at multiple time points, they will be able to assess the degree to which the virus evolves over time. Since virus evolution can occur only if the virus is continuing to replicate, this part of the study will provide an indication of the extent to which antiretroviral therapy can put a stop to the viral life cycle. These studies together will provide an indication of which reservoirs are most responsible for the persistence of the virus, the extent to which antiretroviral therapy can and cannot disrupt those reservoirs, and therefore what remains to be done in targeting reservoirs to cure HIV infection.
University of California San Francisco, San Francisco, CA
Joseph McCune, M.D., Ph.D. – principal investigator
Steven Deeks, M.D. – collaborating investigator
Inflammation and HIV persistence:
Drs. McCune and Deeks will investigate the contribution of ongoing immune activation to the ability of HIV to persist. They hypothesize that a self-perpetuating, looping chain of events is established soon after HIV infection first occurs. The immune system is activated as it attempts to combat the infection, but this immune activation in turn fuels the ability of the virus to replicate and persist, resulting in a situation in which immune activation and viral replication feed one another. One enzyme that has been shown to be associated with AIDS progression is IDO, and Drs. McCune and Deeks believe it may play a critical role in maintaining the positive feedback between immune activation and viral growth. They will test whether disrupting this enzyme reduces the level of immune activation, which would in turn result in a decrease in viral persistence. They will also determine whether patients who naturally maintain extremely low levels of virus also have naturally low levels of IDO. If their hypothesis is correct, the results will point to a potential new therapeutic strategy that could both decrease levels of immune activation— itself associated with some of the disease conditions commonly seen in HIV infection— and lower the amount of virus that persists, bringing us closer to a functional cure.
Johns Hopkins University, Baltimore, MD
Robert Siliciano, M.D., Ph.D. – principal investigator
Janice Clements, Ph.D. – collaborating investigator
Using approved drugs to target latent HIV:
Because HIV can persist indefinitely in reservoirs in an infected individual, eradicating HIV will require flushing virus out of those reservoirs and then targeting it with antiretroviral therapy. Developing new therapeutic agents, such as ones that might flush out latent HIV, can be a timely and costly enterprise, so Drs. Siliciano and Clements are hoping to identify drugs that are already FDA-approved and available for the treatment of other conditions that could be used in the context of HIV infection. They already have one promising lead that they plan to test, both alone or perhaps in conjunction with other agents. These drugs will be tested in two different test-tube settings, one that simulates latent infection in reservoirs, and the other using infected cells that have been extracted from HIV positive patients. In addition, they will use non-human primates to test whether such agents might reduce the amount of virus that is growing or the number of cells that are harboring latent HIV. This model will also allow them to test whether and how latently infected cells throughout the body are affected by such drugs. If successful, these studies could point the way to strategies that could shorten the development time of interventions to cure HIV infection by ten or more years.
Beckman Research Institute of City of Hope, Duarte, CA
John Zaia, M.D. – principal investigator
Quantitating virus in patients receiving either non-ablative or total ablative treatment:
Recently, an HIV patient in Berlin who also had acute leukemia underwent a stem cell transplant from a donor who had a genetic mutation that rendered that donor—and now the patient—resistant to HIV. The extent to which the chemotherapy prior to the transplant may have contributed to the presumed cure is not known, so Dr. Zaia will use a sensitive assay that can measure extremely low levels of virus in patients with AIDS-related lymphoma who have been treated with either partial or aggressive chemotherapy. If cancer chemotherapy can perturb reservoirs of virus, it may provide clues for the development of future therapeutic interventions to cure HIV.