Studies of the course of HIV-1 infection in humans point to an important role of major histocompatibility complex (MHC)-restricted, HIV-specific, cytotoxic T lymphocytes (CTL) in the control of viral burden. At the same time, rhesus macaques challenged SIV or chimeric HIV/SIV viruses (SHIV) have emerged as the best animal model for pathogenesis and vaccine studies a major deficiency of this model is that characterization of SIV/SHIV CTL epitopes and their class I MHC restriction elements in macaques lags significantly behind CTL studies in humans. The goal of this project is to intensively study the MHC allele found in the macaques used for the DNA vaccination studies (described by Dr. Harriet Robinson in Project 1 of this program), providing data essential for an adequate interpretation of the results of those vaccine trials. The three specific aims of this project are: 1) genotypic analysis of the macaque class I MHC alleles (Mamu) using locus-specific PCR primers to clone the macaque cDNAs, followed by development of allele-specific primers for more rapid genotypic analyses; 2) characterization of the peptide binding motifs of the Mamu Class I proteins found at high frequency our colony at the Yerkes Regional Primate Center, leading to testable predictions of CTL epitopes; and 3) production of novel MHC tetramers based on the alleles studied in Aim 2, leading to studies of the frequency and phenotype of the SIV/SHIV- specific CD8+ T cells induced by the vaccination protocol or by challenge infection. Together with the data from the cellular immune response project of this program (Project 4, led by Drs. Villinger and McNichol) and from the clinical course of the SHIV-challenged animals, these data will allow us to determine the epitope-specificity of CTL responses which correlate with protection from viral challenge.
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