HIV 1 SPECIFIC CD4 CELLS IN DISEASE PATHOGENESIS

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DESCRIPTION (Adapted from the Investigator's Abstract): A comparison of HIV infection to other viral diseases in which protective immunity is achieved, reveals that the most glaring defect in HIV-1 infection is the lack of virus-specific CD4 helper cell function. Dr. Walker's laboratory recently identified vigorous HIV-specific CD4 proliferative responses in a subset of long-term non-progressors (LTNP) with extremely low viral loads, providing conclusive evidence that such responses can be elicited by HIV. The investigators hypothesize that CD4 helper cell function is lost in HIV infected persons due to activation and depletion of these cells during the period of peak viremia which accompanies primary infection. Furthermore, they hypothesize that potent antiviral therapy may be able to restore these responses, and the persistence of these cells is a key factor in the maintenance of both the asymptomatic state as well as B cell responses to viral proteins. An additional hypothesis states that dendritic cells are a key factor in leading to selective death of CD4 helper T-cells. To address this latter hypothesis, the P.I. will draw upon the considerable complementary expertise of Dr. Ralph Steinman in the area of dendritic cells and Dr. John Moore in the area of humoral immunity. The collective goal of the IRPG is to learn to generate better resistance to HIV-1. The investigators specifically propose to a) determine the proliferative response to HIV-1 p24 and gp160 in LTNP with low and high viral loads, rapid progressors, and recent seroconvertors; b) determine whether combination antiretroviral therapy administered at the time of seroconversion or during chronic infection can restore HIV-1 specific proliferative responses; c) define helper cell responses in terms of cytokine production and target epitopes, using dendritic cell clusters presenting HIV-1 and CD4 T cells as a source for cloning HIV-specific CD4 cell lines; d) define the role of APC in maintenance of HIV-specific helper cell function; and e) determine whether presentation of infectious virions via dendritic cells leads to selective death of T helper cells.