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（HLA）和趋化因子 受体（CCR）基因对流行病学的影响（即获得和 过程）的HIV-1感染。 该项目将利用1）450 血清转化者（SC）和100名高度暴露的未感染受试者 (EUs)在多中心艾滋病队列研究（MACS）中， 协调研究遗传决定因素的人口基础 两种现象; 2）一组具有广泛专业知识的合作者 在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学以及HLA统计学 分析. 将特别利用 MACS作为检验假说的独特流行病学资源 关于高度多态性的基因项目， 分子分型在HLA区域的任何地方。 HLA分型 点印迹格式的SDCP、ARMS-SSP和SSOP将在 四个实验室，具有通过各种技术进行核查的能力 包括精细分辨率自动测序。 CCR 5及相关 工作将采用荧光素酶报告基因测定，质粒转染， 并结合RT-PCR进行克隆。 广泛的假设是 1）多个连锁的多态性HLA基因编码产物， 与独特的结构特征相互作用， HIV-1感染过程中的大部分变异 也可能影响HIV-1感染的开始，2）共同- 受体基因多态性，如32个碱基对缺失， CCR 5严格控制感染和运动的开始 但对它的进程影响不大。 验证许多 这些假设的各个组成部分，通过广泛的统计 遗传多态性分析表明，影响收购和 HIV-1感染的结果在足够数量的适当 选定的主题将奠定基础的综合模式， 对HIV-1的可变宿主反应。 这些基因研究的结果将 纳入MAC检查病毒复制率的工作 和随时间的变化，免疫病理现象，如T- 细胞稳态和CTL克隆进化，自然史， 临床结果。 阐明了遗传控制 对HIV-1的抗性/易感性应该有助于直接发展 抗逆转录病毒生物制剂（疫苗和免疫调节剂）， 宿主和病毒基因变异，并可能导致更普遍的 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.