Cytotoxic T lymphocytes (CTL) are hypothesized to play a critical role in the host immune response to HIV-1 infection. HIV-1 specific CTL kill virus-infected cells in a MHC-I restricted fashion and release cytokines/chemokines that inhibit viral replication. Our own data indicate these two modes of viral inhibition co-localize in the cytolytic granules of CTL. However, virus infection can lead to downregulation of MHC and consequent protection from CTL. Emerging data indicate that CTL are indeed associated with control of viremia in chronic HIV infection. Data from Ogg et al show that the magnitude of CTL, as determined by a novel flow-based assay which relies on staining of CTL with a tetrameric complex of HLA, beta 2 microglobulin and epitopic peptide, is negatively associated with viral load in untreated persons. However, these studies have only been performed in persons who are HLA A 0201-positive, and have only been performed for two peptide epitopes. Because numerous studies have now shown a link between certain HLA class I alleles and differences in disease progression, it is possible that this same correlation will not hold for all alleles. In addition, recent data from the Walker laboratory suggest that there are epitope-specific differences in the ability of CTL clones to effectively inhibit HIV replication. Furthermore, recent studies in a murine model of chronic viral infection indicate that CTL may exist in vivo that are incapable of carrying out effector function. These recent findings and preliminary data form the basis of a detailed project to assess the role of HLA class I alleles in the CTL response to HIV-1 infection.
Specific aims i nclude: (1) Use HLA class I-peptide tetramers to determine the correlation between CTL and viral load for alleles associated with relative protection (B27, B57), rapid progression (A24, B8), and intermediate progression (A2, A3, and B7); (2) Determine the ability of CTL clones to epitopes restricted by the above alleles to inhibit HIV-1 replication using cells transfected with these alleles as well as peripheral blood mononuclear cells (PBMC); (3) Determine the cytokine/chemokine profiles of CTL to defined epitopes and mechanisms of cell lysis.
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