GENETIC FACTORS IN THE EPIDEMIOLOGY OF HIV1 INFECTION

总体目标是扩大对影响的理解 人类主要组织相容性复合体与趋化因子 受体(CCR)基因的流行病学(即获得性和 当然)HIV-1感染。这项工程将利用450人 血清转换者(SC)和100名高度暴露的未感染参与者 (EUS)在多中心艾滋病队列研究(MACS)中作为 遗传决定因素协同研究的群体基础 两种现象；以及2)具有广泛专业知识的合作者小组 HIV-1流行病学、免疫遗传学、免疫学、蛋白质 建模、数据管理和生物统计，以及人类白细胞抗原统计 分析。将特别利用的规模和范围 MACs作为检验假说的独特流行病学资源 关于可通过详细信息确定的高度多态基因项目 在人类白细胞抗原区域的任何地方进行分子分型。人类白细胞抗原分型依据 点印迹格式的SDCP、ARMS-SSP和SSOP将在 有能力通过各种技术进行验证的四个实验室 包括精细分辨率的自动测序。CCR5及相关 这项工作将采用荧光素酶报告基因分析、质粒转染、 并结合RT-PCR进行克隆。宽泛的假设是 1)编码产物的多个连锁多态的人类白细胞抗原基因 与独特的结构特征相互作用，以确定一个 HIV-1感染过程中变异的很大一部分 可能还会影响HIV-1感染的启动和2)共同 受体基因的多态性，如32个碱基对缺失 CCR5严格控制感染的启动和可识别的运动 但其过程中的影响不那么戏剧性。验证了许多 通过广泛的统计得出这些假设的各个组成部分 遗传多态分析显示影响习得和 在适当数量的适当人群中感染HIV-1的结局 选定的主题将为建立一个全面的 可变宿主对HIV-1的反应。这些基因研究的结果将 被整合到Mac的工作中，以检查病毒复制率 和随时间的变化，免疫致病现象，如T- 细胞动态平衡和CTL克隆进化，自然历史，和 临床结果。阐明玉米赤霉病的遗传控制 对HIV-1的抗药性/敏感性应有助于直接发展 抗逆转录病毒生物制品(疫苗和免疫调节剂) 宿主和病毒的基因变异，可能导致更普遍的 关于病理生物学中遗传多样性的知识。

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.