The overall objectives are to extend understanding of the influence human major histocompatibility complex (HLA) and chemokine receptor (CCR) genes on the epidemiology (I.E. the acquisition and course) of HIV-1 infection. The project will draw upon 1) 450 seroconverters (SCs) and 100 highly exposed uninfected participants (EUs) in the Multicenter AIDS Cohort Study (MACS) as the population base for coordinated research on genetic determinants of both phenomena; and 2) a group of collaborators with wide expertise in HIV-1 epidemiology, immunogenetics, immunology, protein modeling, data management and biostatistics, and HLA statistical analysis. Particular advantage will be taken of the size and scope of the MACS as a unique epidemiologic resource for testing hypotheses about highly polymorphic gene projects identifiable by detailed molecular typing anywhere in the HLA region. HLA typing by SDCP, ARMS-SSP, and SSOP in dot-blot format will be distributed in four laboratories with capacities for verification by various techniques including fine-resolution automated sequencing. CCR5 and related work will employ the luciferase reporter assay, plasmid transfection, and cloning in conjunction with RT-PCR. The broad hypotheses are that 1) multiple, linked polymorphic HLA genes encoding products with distinctive structural characteristis interact to determine a substantial portion of the variation in the course of HIV-1 infection and probably also influence the initiation of HIV-1 infection and 2) co- receptor gene polymorphisms such as the 32-base-pair deletion in CCR5 tightly govern the initiation of infection and exercise discernible but less dramatic effects on its course. Validation of the many individual components of those hypotheses through extensive statistical analysis of genetic polymorphisms shown to influence acquisition and outcome of HIV-1 infection in sufficient numbers of appropriately selected subjects will lay the foundation for a comprehensive model of variable host response to HIV-1. Results of these genetic studies will be integrated into the MACs effort to examine virus replication rates and variation over time, immunopathogenetic phenomena such as T- cell homeostasis and CTL clonal evolution, natural history, and clinical outcomes. Elucidation of the genetic control of resistance/susceptibility to HIV-1 should help direct development of antiretroviral biologics (vaccines and immunomodulators) based on host and viral gene variation and could contribute to more general knowledge about genetic diversity in pathobiology.
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