Promiscuous presentation of HLA class I restricted, HIV derived CTL epitopes CTL mediated cellular immunity is considered an important arm of the host defense against HIV infection and a number of HLA class I alleles have been associated with slow or fast HIV disease progression. Despite some significant advances in the field, the mechanisms by which HLA class I alleles mediate their beneficial or detrimental effects, are still unclear and may include multiple factors such as peptide binding, variability of targeted viral sequences, antigen processing and the kinetics of viral antigen expression. Recent data from murine studies have also linked T-cell receptor (TCR) repertoire diversity with relative control of viral infections. Comparing closely related MHC molecules presenting the identical epitope, these analyses revealed different TCR repertoire diversity depending on which MHC allele presented the targeted epitope and indicated that a narrow TCR repertoire was associated with CTL responses of low functional avidity and inability to control viral replication. Based on these recent reports and our own, extensive preliminary recent data, the present proposal aims to identify HIV encoded, promiscuously binding CTL epitopes that can be presented by HLA alleles differentially associated with HIV disease progression and to assess the functional avidity and TCR repertoire diversity of these CTL responses, depending on which allele the epitope is presented. Functional avidity and TCR repertoire diversity are then put in relation with the CTL's ability to efficiently recognize naturally occurring viral epitope variants and to drive viral evolution in response to immune selection pressure mediated by epitope presentation on alleles associated with wither fast or slow disease progression. Focusing on promiscuously binding CTL epitopes, the potential association between TCR repertoire diversity, functional avidity and rate of HIV disease progression can be assessed in the absence of a number of confounding effects that have limited similar analyses in the past. The emerging data will be of significant importance for HIV vaccine development and help the identification of true immune correlates of protective HIV immunity.
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