This project is based on the hypothesis that cellular immune reactivities which occur early in response to HIV-1 infection play a major role in the resolution of peak plasma viremia, suppression of viral replication, and the control of viral pathogenesis. The overall goal of the proposed studies is to provide comprehensive prospective and retrospective analyses of cellular immune reactivities present at frequent intervals throughout the acute phase of HIV-1 infection, utilizing patient materials generated from both the Trinidad HEX 4 and planned prospective cohorts. Unlike previous studies, these endeavors will include both symptomatic and asymptomatic seroconvertors. A major effort will be made to establish a hierarchy of the early cytotoxic T-lymphocyte (CTL) responses to HIV-1 with respect to ontogeny, overall magnitude, and viral specificity. To examine relevant CTL reactivities against autologous viral isolates, a targeting strategy involving infection of autologous BLCL and/or CD4 cells will be utilized. The activation of T-cells during the acute phase of HIV-1 infection will be explored in depth through the use of an extensive panel of phenotypic markers. Activation patterns as well as cytokine gene expression will be delineated for both CD4+ and CD8+ T-cell subsets. Preferential bias in the T-cell response of seroconvertors will also be followed through analysis of T-cell receptor (TcR) vbeta usage by both CD4 and CD8 cells. The overall integrity of MHC class II responses to recall antigens will be investigated, as will the ontogeny of HIV-1 specific CD4 responses during the acute phase. Although not strictly a cellular reactivity, studies on the ontogeny and specificity of ADCC reactivities will also be performed. The phenomenon of CD8+ cell-mediated, non- cytolytic suppression of viral replication will be examined in relation to early events in HIV-1 infection. These studies will focus on issues of quantitation and specificity for autologous versus heterologous isolates and will involve analysis at the level of virus production. For all of these studies attempts will be made to examine any possible correlations between these broad cellular immune reactivities and control of virus as reflected in the peripheral virus load of each seroconverting patient. Collectively, these studies will greatly extend our current understanding of the correlates of immune protection as well as pathogenic consequences as they relate to early cellular immune responses to HIV-1.
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