Research Interests

My broad interest is the pathogenesis of human immunodeficiency virus type 1 (HIV-1). The general approach we have taken is to identify clinical circumstances that may reveal the critical elements of pathogenesis. Our studies look at both virus and host factors that could play a role in the disease process.

We are examining the rare individuals who show no evidence of disease 10 or more years after infection with HIV-1 without ever having received antiretroviral therapy. We have found evidence that the viruses of many of these long-term non-progressors (LTNP) have unique characteristics (1). We have observed unusual or unique genetic polymorphisms that are difficult for the virus to revert (mainly small deletions or insertions), and are present with uniform consistency over time. We are examining the possibility that these polymorphisms affect the pathogenic potential of the viruses. We also have shown that the LTNP as a group have vigorous cellular immune responses (2). We are developing techniques to measure virus-specific cellular immune responses in order to test the hypothesis that certain immune responses are critical in limiting the growth of virulent strains in the LTNP. With these studies we aim to define the relative importance and functional contribution of individual genetic elements of HIV-1 for pathogenesis in humans. We also seek to identify immune mechanisms by which HIV-1 infection or disease might be controlled.

We are also examining the predictors of disease progression in individuals on highly active antiretroviral therapy (HAART). Using a sensitive assay to detect 2-LTR circular forms of viral DNA in circulating lymphocytes, we have found evidence that most individuals with undetectable plasma viral RNA still have newly infected cells in the circulation (5). We have enrolled into a longitudinal cohort study individuals who are receiving HAART and who have had undetectable levels of plasma viral RNA for greater than one year. Our primary goal is to identify factors that predict disease progression in this group. We also will attempt to define the residual reservoirs of viral replication in these individuals. With these studies we will gain further insight into HIV-1 pathogenesis in the setting of HAART. These studies may provide new benchmarks for patients and clinicians striving to achieve optimal clinical outcome.