Biography
Dr. Robert F. Siliciano is Professor of Medicine at the Johns Hopkins University School of Medicine. He received his BA from Princeton in 1974 and then completed an MD and a PhD in Immunology at Johns Hopkins. After a postdoctoral fellowship at Harvard Medical School with Ellis Reinherz, he returned to Johns Hopkins. His research has focused on AIDS vaccine development and mechanisms of HIV persistence in patients on combination antiretroviral therapy. His group has identified a latent reservoir for HIV in resting memory CD4+ T cells that allows the virus to persist indefinitely despite strong antiviral immune responses and potent antiretroviral therapy. The discovery of this reservoir has led to a major change in strategies for the treatment of HIV infection, with a shift towards a more conservative approach to the initiation of therapy now that eradication of the infection with antiretroviral drugs no longer a realistic goal. His group is currently working on strategies for optimizing the treatment of HIV infection. Dr. Siliciano is the recipient of an NIH Merit Award and has served as chair of the NIH Study Section on AIDS and Related Research. At Johns Hopkins, he directs the MD-PhD program.
Abstract
Latent Reservoirs for HIV-1: Basic Mechanisms and Clinical Significance
Treatment of HIV infection with combinations of antiviral drugs ("cocktail therapy") represents the best current hope for prolonging the lives of the staggering number of people infected with this virus. In many patients, this form of treatment drop levels of the free virus in blood down so far that they can no longer be detected using even the most sensitive of current blood tests. The dramatic effect of combination therapy on free virus levels initially raise hopes that prolonged treatment might cure the infection. However, work from our laboratory has shown that in the vast majority of patients, treatment cannot cure the infection because the virus perists in a silent form in a very stable reservoir of long lived T cells. The discovery of a silent or latent reservoir for HIV that allows lifetime persistence of the virus in most patients has led many physicians to rethink the overall strategy for the treatment of HIV infection. New guidelines suggest that it may be better to delay the initiation of treatment with potentially toxic drug combinations now that virus eradication no longer appears possible. Most recently, we have shown that although combination therapy is unlikely to be curative, it can come close to stopping the evolution of the virus. The overall objective of the proposed studies is to use new information about how HIV persists to develop new approaches and strategies for treatment. The first goal is to develop a way to determine whether the virus is still evolving. A major problem is that the virus rapidly evolves to become resistant to the treatment drugs. With better ways of detecting viral evolution, it should become easier to select the drug combination that do the best job of stopping the evolution of the virus with the fewest side effects for the patient. In addition, this assay will be useful in deciding when therapy needs to be changed. A second major goal is to improve the treatments available for patients who already have developed resistance to some AIDS drugs. Some of the resistant virus can be present in a silent form, making it difficult for physicians to know which drugs to chose. We will attempt to develop new approaches that give a complete picture of the drug resistant viruses present in a patient, including those stored in the latent reservoir. In addition, we will develop ways for physicians to test various alternative combinations of antiviral drugs for ability to inhibit growth of the patient’s virus in the test tube. We hope that this will facilitate the selection of treatments for patients whose options have been narrowed by the evolution of drug resistance.