Although development of an effective AIDS vaccine to provide sterilizing immunity remains an elusive goal, vaccine protection from disease progression has been achieved in animal models, supporting this approach as a realistic goal for first generation vaccines for humans. Expanding evidence indicates that events in the acute stage of infection determine long-term outcome, and that HIV-specific CD8 T cells are critical for containment of viral replication. Major challenges persist, including the tremendous HIV diversity among strains, and that the relative contributions of individual responses to immune containment in acute infection and over the course of disease are not known. This is now an even more critical issue given the failure of a recent phase lib study of a CTL based vaccine, which was recently shown to be ineffective in influencing viral set point after infection, despite the induction of strong CDS T cell responses by IFN-y Elispot. During the past funding period, we have worked closely with each of the other PLs on this PO1 to generate preliminary data indicating that only a subset of HLA alleles and epitopes participate in the acute phase CD8 T cell response;that antigen processing contributes to immunodominance by favoring the production of certain epitopes over others;that some anti-HIV responses contribute to immune containment, whereas others act as """"""""passengers"""""""", appearing to simply increase with increasing viral load;and that the ability to kill infected target cells and inhibit autologous viral replication vary widely among HIV-specific CDS T cell responses but are not reflected in currently used Elispot assays. In addition, by linking detailed viral sequencing studies with immunologic assays, we have shown that escape occurs within a predictable subset of epitopes in acute infection, with predictable amino acid changes and in part predictable kinetics. Together these data indicate that the most important targets of the initial response are limited and definable, as are the earliest escape mutations that arise. This project is highly integrated with the other projects being proposed, and focuses on factors shaping the initial immunodominance patterns and on the functional antiviral activity of CDS T cells that is quantifiable. Specifically, we propose to: 1) Define the immunodominant CDS T cell epitopes and restricting HLA alleles in persons with acute HIV infection that contribute to the initial CDS T cell responses, and the predictable mutations that arise within these epitopes, 2) Define the impact that antigen processing has on determining the immunodominance patterns of the initial HIV-1-specific CD8+ response, and 3) Determine the relative ability of CDS T cells targeting different epitopes and restricted by different alleles to inhibit viral replication.
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