GENETIC FACTORS IN THE EPIDEMIOLOGY OF HIV1 INFECTION

HIV1 感染流行病学中的遗传因素

• 批准号: 6171040
• 负责人: Richard Alan Kaslow
• 金额: $ 27.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2002-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171040
• 关键词: HIV infections; cytokine receptors; disease /disorder proneness /risk; epidemiology; gene expression; genetic polymorphism; human genetic material tag; human immunodeficiency virus 1; major histocompatibility complex; molecular cloning; molecular pathology; nucleic acid sequence

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.

总体目标是加深对影响的理解 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 HIV-1感染的过程）。 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参与者 (EU) 在多中心艾滋病队列研究 (MACS) 中作为 遗传决定因素协调研究的人口基础 两种现象； 2) 一群具有广泛专业知识的合作者 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 分析。 将特别利用其规模和范围 MACS 作为检验假设的独特流行病学资源 关于可通过详细识别的高度多态性基因项目 HLA 区域任何位置的分子分型。 HLA 分型 点印迹格式的 SDCP、ARMS-SSP 和 SSOP 将在 四个具有各种技术验证能力的实验室 包括精细分辨率自动测序。 CCR5及相关 工作将采用荧光素酶报告基因测定、质粒转染、 并与 RT-PCR 结合进行克隆。 广泛的假设是 1) 多个连锁多态性 HLA 基因编码产物 具有独特的结构特征相互作用以确定 HIV-1 感染过程中变异的很大一部分 也可能影响 HIV-1 感染的开始和 2) 受体基因多态性，例如 32 个碱基对缺失 CCR5 严格控制感染的起始和可识别的运动 但对其进程的影响较小。 多方验证 这些假设的各个组成部分通过广泛的统计 分析显示影响获得和获得的遗传多态性 足够数量的适当人群感染 HIV-1 的结果 选定的科目将为综合模型奠定基础 宿主对 HIV-1 的反应不同。 这些基因研究的结果将 纳入 MAC 工作以检查病毒复制率 以及随时间的变化、免疫致病现象，如 T- 细胞稳态和 CTL 克隆进化、自然历史和 临床结果。 阐明基因控制 对 HIV-1 的耐药性/易感性应有助于直接发展 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可能有助于更普遍的 有关病理学遗传多样性的知识。