Accumulating evidence suggests that robust HCV-specific CD4+ helper responses and CD8+ T cell responses are necessary for resolution of infection. Studies from the previous funding period demonstrated that CD4+ T cell-depleted animals developed chronic infection after virus rechallenge. Our studies over the prior funding period demonstrate a link between the diversity of T cell receptor (TCR) repertoires directed against dominant viral epitopes, and resolution of infection. Resolved infection was associated with diverse TCR repertoires directed against dominant CD4+ and CD8+ T cell epitopes. In contrast, chronic infection was associated with lack of CD4+ T cell responses, and narrow TCR repertoires directed against CD8+ T cell epitopes. These narrowly directed responses preceded immune escape and establishment of chronic viral infection. We hypothesize that diverse TCR repertoires directed against dominant epitopes arise early after acute infection, and are beneficial for at least 2 reasons. First, diverse TCR repertoires are far more likely to include TCR clonotypes able to recognize potential epitope variants, thus limiting immune escape. Second, the early generation of a diverse repertoire may include the expansion of TCR clonotypes with high avidity for the peptide/MCH complex. The studies in this project will directly complement the functional and phenotypic studies performed in project one, and will allow us to directly test these hypotheses in a highly relevant animal model. We propose to test this hypothesis with the following specific aims:
Specific aim 1 : Determine whether the generation of diverse epitope-specific CD4+ TCR repertoires predict resolution of HCV infection.
Specific aim 2 : Determine whether the generation of diverse epitope-specific CD8+ TCR repertoires predict resolution of HCV infection, and whether the maintenance of CD8+ T cell responses is dependent upon the maintenance of CD4+ T cell responses with diverse TCR repertoires.
Specific aim 3 : Determine whether transmission of HCV variants containing escape mutations in dominant MHC class I or II epitopes escape immune recognition from existing TCR repertoires in animals with resolved HCV.
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