University of Washington School of Public Health
Professor, Medicine - Allergy and Infectious Dis.
Fred Hutchinson Cancer Research Center
Protection and Control of HIV-1 Infection by T Cell Immunity.
My laboratory seeks to identify the components of immunity that are important in preventing and controlling HIV-1 infection. Our investigations focus on HIV-specific CD4+ and CD8+ T cells,since these are critical in controlling most viral infections. We wish to know how HIV-specific T cells are induced in natural infection and by immunization, and what properties confer containment or eradiation of HIV-1.
Our studies encompass a broad range of clinical research investigations in patients who experience unusual control of HIV-1 infection. These include 1) individuals with acute infection, who typically demonstrate a rapid decline in plasma viremia with the onset of T cell responses,2) persons with long-term non-progressive disease, who control infection for more than a decade without antiretroviral treatment, and more recently 3) patients from Senegal who have HIV-2 infection, which leads to a more attenuated infection than HIV-1 and appears to reduce the virulence of HIV-1 infection if co-infected. In addition, we investigate the role of HIV-1-specific memory T cells in protecting HIV-1-seronegative persons with multiple high risk exposures to HIV-1. Insights from these studies have direct application to vaccine development, particularly in understanding the frequency and breadth of MHC-restricted class I CD8+ cytotoxic T cells. Our initial studies demonstrated that a broad suppression of T helper function occurs during acute infection, but a progressive recovery ensues over the next months as virus load stabilizes. However, HIV-1-specific CD4+ T cells are difficult to detect unless very early in infection, and the TCR repertoire is disturbed soon after infection. Accompanying these changes are CD8+ T cell cytotoxic activities recognizing both variable and conserved epitopes within multiple HIV-1 genes. Currently, we are exploring the mechanisms leading to HIV-1-specific CD4+ T cell dysfunction and ways to alter this through therapy. In addition, we wish to understand the specificity, breadth and effector activities of CD8+ T cells that control the initial reduction in viremia following acute infection. The long-term non-progressors represent a very heterogeneous group, and many have intermittent spikes of viremia that are contained by antigen-specific CD8+ T cells in conjunction with a strong CD4+ T helper response. Current studies are determining the specificities of these responses to autologous viral isolates. Among a few seronegative persons persistently exposed to HIV-1 with sustained T cell responses, we found very low copy numbers of HIV-1 in resting CD4+ T cells.
Additional studies seek to determine if low level infection is a common feature among this study group, if the viruses are replication-incompetent and if T cells contribute to the containment of infection. We have also directed our investigations to understand the local T cell response at the initial sites of infection. We found that epitope specificities and TCR usage are similar in mucosal CD8+ T cell effectors as those circulating in peripheral blood. Moreover, induction of mucosal T cells can occur with systemic immunization. These results suggest that memory T cells home to areas where HIV-1is acquired or transmitted and that their functional properties are similar to those in the circulation.
MD Medicine, Medical University of South Carolina, 1980
PhD Pathology, Medical University of South Carolina, 1978
BS Biology, Furman University, 1973
In the News
- Clues for Future HIV Vaccines
New England Journal of Medicine, 11/28/2013
- Another Experimental AIDS Vaccine Fails, But That's Progess in Science