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.

总体目标是扩展对影响的理解 人类主要的组织相容性复合物（HLA）和趋化因子 流行病学的受体（CCR）基因（即获取和 HIV-1感染的过程。 该项目将利用1）450 血清发电机（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（MAC）中 对遗传决定因素的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 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 分析。 将对大小和范围的特殊优势 Mac是用于测试假设的独特流行病学资源 关于高度多态基因项目可通过详细信息识别 分子键入HLA区域的任何地方。 HLA打字 SDCP，ARMS-SSP和SSOP以点印刷格式将分布在 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一起克隆。 广泛的假设是 1）编码产物的多个链接的多态性HLA基因 具有独特的结构特征相互作用以确定 HIV-1感染过程中的大量变异部分 并且可能影响HIV-1感染的启动和2） 受体基因多态性，例如32碱基的缺失 CCR5紧紧控制感染和运动的开始 但是对其课程的影响较小。 验证许多 通过广泛的统计，这些假设的个体组成部分 对遗传多态性的分析，这些遗传多态性影响会影响获取和 HIV-1感染的结果适当数量 选定的主题将为一个综合模型奠定基础 可变主机对HIV-1的响应。 这些遗传研究的结果将 集成到Macs努力检查病毒复制率 和随着时间的变化，免疫发育现象，例如T- 细胞稳态和CTL克隆进化，自然历史和 临床结果。 阐明的遗传控制 对HIV-1的抵抗/敏感性应有助于直接发展 基于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 关于病理生物学中遗传多样性的知识。