Molecular Analysis of HCV-specific T Cell Responses

越来越多的证据表明，强大的hcv特异性CD4+辅助反应和CD8+ T细胞反应是解决感染所必需的。先前资助期的研究表明，CD4+ T细胞耗尽的动物在病毒再攻击后出现慢性感染。我们在先前资助期的研究表明，针对显性病毒表位的T细胞受体（TCR）谱的多样性与感染的解决之间存在联系。解决感染与针对显性CD4+和CD8+ T细胞表位的多种TCR相关。相比之下，慢性感染与缺乏CD4+ T细胞反应和针对CD8+ T细胞表位的狭窄TCR谱有关。这些狭窄的定向反应先于免疫逃逸和慢性病毒感染的建立。我们假设出现了针对显性表位的不同TCR谱

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.