HLA-ALL IN THE CELLULAR IMMUNE RESPONSE TO HIV-1

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DESCRIPTION (Abstract): A major goal of vaccine research for prevention of AIDS is to determine the immune correlates of protection against HIV-1 infection. In this context, our proposal seeks to understand how HLA-A*1101 (HLA-A11), a significantly prevalent class I MHC molecule in a cohort of Thai Highly Exposed Persistently Seronegative (HEPS) brothel workers, and the most common HLA-A locus allele in South East Asia (SEA), functions in relation to protective immunity to HIV-1 infection. Our hypothesis is that it may relate, at least in part, to the way this class I allele binds cytotoxic T lymphocyte (CTL) epitopes and presents them to T cell receptors (TCRs). To test this hypothesis, we propose a biochemical and crystallographic analysis of HLA-A11 complexed with single HIV-1 peptides. These peptides will be selected based on results from our CTL studies in Thai HLA-A11-positive HIV-infected and HEPS individuals. The HIV-A11-restricted epitopes which are immunodominant in both of these donor groups, and conserved between the predominant North American clade B and major Thai clade E strains of HIV-1, will be the initial focus of these studies. Since CD8+ CTLs play a critical role in the initial immune responses to HIV-1 infection, a molecular characterization of HLA-A11 complexed with immunodominant HIV-1 peptides is important and relevant to understand the nature of HLA-A11-restricted CTL responses in these cohorts. The long-term objective of this study is to identify natural mechanisms potentially able to confer resistance to HIV-1 infection and provide a structural framework for the design of peptide-based HIV-1 vaccines capable of reproducing these apparent protective states of immunity. Knowledge derived from these studies will therefore be useful in relation to HIV-1 infection and other infectious diseases prevalent in SEA where this allele is extremely common.