Genetic Factors in the Epidemiology of HIV-1 Infection

HIV-1 感染流行病学中的遗传因素

• 批准号: 6640625
• 负责人: Richard Alan Kaslow
• 金额: $ 36.25万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640625
• 关键词: AIDS; African; HIV infections; Hispanic Americans; antigen presentation; caucasian American; clinical research; cytokine receptors; cytotoxic T lymphocyte; epidemiology; gender difference; gene interaction; genetic polymorphism; human immunodeficiency virus 1; human subject; immunogenetics; immunoregulation; interleukin 10; linkage disequilibriums; macrophage inflammatory proteins; major histocompatibility complex; pathologic process; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism; tumor necrosis factor alpha; virus load; virus replication

Human genetic polymorphism influences occurrence and evolution of HIV/AIDS. The long-range goal of this comprehensive bench-to-population investigative approach is to explain why some individuals escape HIV infection or control it better than others. Broadly, the project aim is to construct analytic models of the cumulative effects of the growing number of polymorphisms on three critical endpoints: 1) acquisition of infection, 2) relatively early equilibration of virus and host, as measured by plasma concentration of HIV RNA (viral load), and 3) rate of progression to AIDS. Comparisons will be made in populations with different ethnicity and HIV exposure. Epidemiologic documentation of the influence of specific polymorphisms is essential to collaborations with other laboratory scientists to explore functional correlates of sequence variation. Comprehensive knowledge of the frequency of major contributory variants and the magnitude of their effects will have noteworthy health impact: it should inform vaccine development, particularly by directing immunologists toward HLA allele-HIV antigenic peptide combinations favorable for cytotoxic T-lymphocyte (CTL) and T-helper response, and it should eventually guide clinical decision-making either in the context of patient care or in assessing the genetic impact at the population level. In the near term, the proposed initiative will build on previous success by demonstrating the importance of variants in genes of the antigen-processing and -presenting (HLA and TAP) and HIV-1 coreceptor (CCR) pathways and by targeting additional polymorphic loci related to immune surveillance (MICA, HLA-E, TAPBP and CTLA4), to HIV-1 penetration/pathogenesis (SYCA3-5), and to immune regulation (TNF and IL10). Investigators will use sequence-specific primers (SSP), restriction fragment-length polymorphism (RFLP), PCR-based sequencing, reference-strand conformation analysis (RSCA), and other state-of-the art technology to detect known and new polymorphisms within the selected loci. The collaboration between epidemiologists and molecular geneticists in three previously studied cohorts of largely Caucasian homosexual men will extend to multiple cohorts with at least 1640 untreated males and females, including Africans and African-Americans and adolescents as well as additional treated patients. Joint effects of multiple variants on the designated endpoints will be examined, specialized statistical procedures for assessing contributions of ethnic heterogeneity, linkage disequilibrium with emphasis on novel haplotype assignment strategy with "haplotype tagging" SNPs, and gene-gene interaction.

人类基因多态性影响艾滋病毒/艾滋病的发生和演变。 这种全面的针对人群的调查方法的长期目标是解释为什么有些人比其他人更容易逃脱艾滋病毒感染或控制得更好。 总体而言，该项目的目标是构建分析模型，说明越来越多的多态性对三个关键终点的累积影响：1) 获得感染，2) 病毒和宿主相对较早的平衡，通过血浆 HIV RNA 浓度进行测量（病毒载量），以及 3） 艾滋病进展率。 将对不同种族和艾滋病毒暴露人群进行比较。 特定多态性影响的流行病学记录对于与其他实验室科学家合作探索序列变异的功能相关性至关重要。对主要变异的频率及其影响程度的全面了解将对健康产生显着的影响：它应该为疫苗开发提供信息，特别是通过指导免疫学家研究有利于细胞毒性 T 淋巴细胞 (CTL) 和 T 细胞的 HLA 等位基因 - HIV 抗原肽组合。 -辅助反应，它最终应该在患者护理或评估人群水平的遗传影响方面指导临床决策。 在短期内，拟议的举措将在先前成功的基础上，通过证明抗原加工和呈递（HLA和TAP）和HIV-1辅助受体（CCR）途径基​​因变异的重要性，并通过针对相关的其他多态性位点免疫监视（MICA、HLA-E、TAPBP 和 CTLA4）、HIV-1 渗透/发病机制（SYCA3-5）以及免疫调节（TNF 和 IL10）。 研究人员将使用序列特异性引物 (SSP)、限制性片段长度多态性 (RFLP)、基于 PCR 的测序、参考链构象分析 (RSCA) 和其他最先进的技术来检测已知和新的多态性选定的基因座。 流行病学家和分子遗传学家之前在三个主要由白人同性恋男性组成的队列中进行的合作研究将扩展到包含至少 1640 名未经治疗的男性和女性的多个队列，其中包括非洲人、非裔美国人和青少年以及其他接受治疗的患者。 将检查多个变体对指定终点的联合效应，用于评估种族异质性、连锁不平衡的贡献的专门统计程序，重点是具有“单倍型标记”SNP 的新型单倍型分配策略以及基因-基因相互作用。