Dr. M. Juliana McElrath

Protection and Control of HIV-1 Infection by T Cell Immunity.

The mission of our laboratory is 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. Our goal is to understand how HIV-specific T cells are induced both 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 individuals with acute infection who typically demonstrate a rapid decline in plasma viremia with the onset of T cell responses; individuals with long-term non-progressive disease who control infection for more than a decade without antiretroviral treatment; and, more recently, individuals 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 when individuals are co-infected. Additionally, 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. Our further efforts are directed toward understanding what elements of immunity correlate with protection against HIV-1 infection by vaccine. 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 cell helper function occurs during acute infection, but a progressive recovery ensues over the following months as virus load stabilizes. However, HIV-1-specific CD4+ T cells are difficult to detect unless they are seen 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 are attempting 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 cell 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. Further studies seek to determine if this low level infection is a common feature in 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 understanding 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 to those circulating in peripheral blood. Moreover, induction of mucosal T cells can occur with systemic immunization, suggesting that memory T cells home to areas where HIV-1 is acquired or transmitted and that their functional properties are similar to those in the circulation.