Genetic Factors in the Epidemiology of HIV-1 Infection

人类基因多态性影响HIV/AIDS的发生和发展。 这种全面的对人群的调查方法的长期目标是解释为什么有些人逃避艾滋病毒感染或控制它比其他人更好。 从广义上讲，该项目的目标是构建越来越多的多态性对三个关键终点的累积效应的分析模型：1）感染的获得，2）病毒和宿主的相对早期平衡，如通过HIV RNA（病毒载量）的血浆浓度测量的，和3）进展为艾滋病的速度。 将在不同种族和艾滋病毒暴露的人群中进行比较。 特定多态性影响的流行病学文献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。全面了解主要促成变量的频率及其影响程度将对健康产生显著影响：它应该为疫苗开发提供信息，特别是通过指导免疫学家开发有利于细胞毒性T淋巴细胞（CTL）和辅助性T细胞应答HLA等位基因-HIV抗原肽组合，它最终应该指导临床决策，无论是在病人护理的背景下，还是在人口水平上评估遗传影响。 在短期内，拟议的倡议将建立在以前的成功，证明变异的重要性，基因的抗原加工和呈递，（HLA和TAP）和HIV-1辅助受体（CCR）途径，并通过靶向与免疫监视相关的其他多态性位点（云母、HLA-E、TAPBP和CTLA 4）、HIV-1渗透/发病机制（SYCA 3 -5）和免疫调节（TNF和IL 10）。 研究者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所选基因座内的已知和新多态性。 流行病学家和分子遗传学家在三个先前研究的主要是白人同性恋男性的队列中的合作将扩展到多个队列，其中至少有1640名未经治疗的男性和女性，包括非洲人和非洲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影响，用于评估种族异质性贡献的专门统计程序，连锁不平衡，重点是使用“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。

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.