Genetic Factors in the Epidemiology of HIV-1 Infection

人类基因多态影响HIV/AIDS的发生和演变。这种从人群到人群的综合调查方法的长期目标是解释为什么一些人逃脱了艾滋病毒感染或比其他人更好地控制艾滋病毒感染。广泛地说，该项目的目标是构建分析模型，以分析越来越多的多态对三个关键终点的累积影响：1)感染的获得，2)病毒和宿主相对较早的平衡，以艾滋病毒RNA(病毒载量)的血浆浓度衡量，以及3)发展为艾滋病的速度。将在不同种族和艾滋病毒暴露的人群中进行比较。对特定多态的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是至关重要的。全面了解主要致病变异的频率及其影响的大小将对健康产生显著的影响：它应该为疫苗开发提供信息，特别是通过引导免疫学家研究有利于细胞毒性T淋巴细胞(CTL)和T辅助反应的HLA等位基因-HIV抗原肽组合，并最终指导临床决策，无论是在患者护理的背景下还是在人群水平上评估遗传影响。在短期内，拟议的倡议将在以往成功的基础上，通过展示抗原处理和呈递(HLA和TAP)和HIV-1共受体(CCR)途径基因变异的重要性，并通过瞄准与免疫监测(MICA、HL A-E、TAPBP和CTLA4)、与HIV-1渗透/致病(SYCA3-5)和免疫调节(TNF和IL10)相关的额外多态基因座，来进一步发展这一倡议。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选定基因座中的已知和新的多态。流行病学家和分子遗传学家在之前研究的三个主要是高加索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名未接受治疗的男性和女性，包括非洲人、非裔美国人和青少年以及额外接受治疗的患者。将研究多个变异对指定终点的联合影响，评估种族异质性、连锁不平衡的贡献的专门统计程序，重点是利用单倍型标记SNPs的新单倍型分配策略，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.