Genetic Factors in the Epidemiology of HIV-1 Infection

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Human genetic polymorphism influences occurrence and evolution of HIV/AIDS. The long-range goal of this comprehensive bench-to-population investigative approach is to explain why some individuals escape HIV infection or control it better than others. Broadly, the project aim is to construct analytic models of the cumulative effects of the growing number of polymorphisms on three critical endpoints: 1) acquisition of infection, 2) relatively early equilibration of virus and host, as measured by plasma concentration of HIV RNA (viral load), and 3) rate of progression to AIDS. Comparisons will be made in populations with different ethnicity and HIV exposure. Epidemiologic documentation of the influence of specific polymorphisms is essential to collaborations with other laboratory scientists to explore functional correlates of sequence variation. Comprehensive knowledge of the frequency of major contributory variants and the magnitude of their effects will have noteworthy health impact: it should inform vaccine development, particularly by directing immunologists toward HLA allele-HIV antigenic peptide combinations favorable for cytotoxic T-lymphocyte (CTL) and T-helper response, and it should eventually guide clinical decision-making either in the context of patient care or in assessing the genetic impact at the population level. In the near term, the proposed initiative will build on previous success by demonstrating the importance of variants in genes of the antigen-processing and -presenting (HLA and TAP) and HIV-1 coreceptor (CCR) pathways and by targeting additional polymorphic loci related to immune surveillance (MICA, HLA-E, TAPBP and CTLA4), to HIV-1 penetration/pathogenesis (SYCA3-5), and to immune regulation (TNF and IL10). Investigators will use sequence-specific primers (SSP), restriction fragment-length polymorphism (RFLP), PCR-based sequencing, reference-strand conformation analysis (RSCA), and other state-of-the art technology to detect known and new polymorphisms within the selected loci. The collaboration between epidemiologists and molecular geneticists in three previously studied cohorts of largely Caucasian homosexual men will extend to multiple cohorts with at least 1640 untreated males and females, including Africans and African-Americans and adolescents as well as additional treated patients. Joint effects of multiple variants on the designated endpoints will be examined, specialized statistical procedures for assessing contributions of ethnic heterogeneity, linkage disequilibrium with emphasis on novel haplotype assignment strategy with "haplotype tagging" SNPs, and gene-gene interaction.