Host Genetic Epidemiology in HIV-1-Discordant African Couples and Other Cohorts

HIV-1 不一致的非洲夫妇和其他群体的宿主遗传流行病学

• 批准号: 7422058
• 负责人: Richard Alan Kaslow
• 金额: $ 72.68万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422058
• 关键词: 17q11; 19q13.4; 3p21; AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; African; African American; Alleles; Ancillary Study; Antigen Presentation; Antigens; Arts; Bioinformatics; CCL3 gene; CCL3L1 gene; CCL4 gene; CCR; CCR5 gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Cells; Cellular Immunity; Chromosomes, Human, Pair 3; Class; Classification; Clinical; Collaborations; Complex; Copy Number Polymorphism; Couples; Critical Pathways; Cytotoxic T-Lymphocytes; DNA Sequence; Data; Depth; Development; Disease; Epidemiologic Studies; Ethnic Origin; European; Evolution; Family; Frequencies; Gene Family; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genomics; Goals; HIV; HIV vaccine; HIV-1; HLA Class I Genes; HLA G antigen; HLA-A Antigens; HLA-A gene; HLA-A2 Antigen; HLA-B Antigens; HLA-C Antigens; Haplotypes; Health; Heterosexuals; Histocompatibility Antigens Class I; Human; Human Genetics; Immune; Immune Response Genes; Immunogenetics; Immunologics; Individual; Infection; Infection Control; Interruption; Intervention Trial; Investigation; Joints; Knowledge; Laboratories; Leukocytes; Ligands; Link; MHC Class I Genes; Mediating; Modeling; Monitor; Natural Killer Cells; Natural experiment; Nature; Outcome; Outcome Measure; Pathway interactions; Phenotype; Plasma; Population; Portraits; RANTES; Rate; Reporting; Research; Research Infrastructure; Research Project Grants; Resources; Risk; Role; Rwanda; Sample Size; Scientist; Services; Shapes; Single Nucleotide Polymorphism; Solid; Specimen; Staging; Statistical Methods; System; Techniques; Testing; Time; Translating; Uganda; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Virus; Work; Zambia; base; beta-Chemokines; biomedical scientist; chemokine; chemokine receptor; cohort; cytotoxicity; design; gene environment interaction; genetic epidemiology; genetic variant; genome database; immunoregulation; indexing; innovation; insight; men who have sex with men; microbicide; novel; receptor; repository; response; tool; transmission process; viral RNA

DESCRIPTION (provided by applicant): Human genetic polymorphisms influence the occurrence and evolution of HIV-1 infection. The goals of the Office of AIDS Research FY 2008 Plan for HIV-Related Research include the identification of host genetic factors that explain highly variable responses to the infection and its sequelae. This proposed initiative will provide new insight into key genetic determinants of these responses. This new knowledge will translate into guidance for vaccinologists grappling with the development of HIV vaccines and potential population differences in response to them, for biotechnologists pursuing strategies for immunomodulation of co-receptor and ligand molecules, and for clinicians designing and analyzing intervention trials. Genetic determinants will be studied primarily in infected and susceptible populations in Zambia, Uganda, and Rwanda and secondarily in European and African-American HIV/AIDS cohorts. Primary work will concentrate on a unique assembly of 1400 heterosexually active African couples who are discordant for HIV-1 infection (i.e., one partner HIV-1- positive and one negative). Through investigation of couples, responses of two hosts successively infected with related virus can be observed on a previously unequaled scale. This natural experiment permits powerful hypothesis testing for genetic effects on transmission and viral evolution in initially untreated individuals. Specific aims address genes in two pathways critical for the response to the virus. The first aim covers genes in the HLA class I antigen-presenting pathway (HLA-A, HLA-B and HLA-C) along with those in the leukocyte receptor complex (LRC) gene family including KIR genes and LILRB1 in the natural killer cell pathway. The second aim covers genes in the pathway for expression of the HIV-1 chemokine co-receptor and its ligands (CCR2, CCR5, CCL3, CCL3L1, CCL4, CCL4L1, and CCL5). Related new candidate genes will be considered. Public bioinformatics databases, genome-level sequencing services, and state-of-the-art laboratory techniques will be used to detect polymorphisms within the selected loci. Principal outcome measures include time to seroconversion in exposed HIV-1-negative partners and level of plasma viral RNA early in infection. Individual African cohorts will support independent hypothesis-testing, and powerful inferences may be drawn from data on judiciously aggregated cohorts. Analyses will emphasize predicted interactions between products of receptor and ligand genes. Simultaneous effects of multiple markers on outcomes will be examined. Comparisons effects across HIV-1 subtypes within Africans and across ethnic boundaries will be made. Through the application's innovative statistical approaches that take advantage of haplotype recognition, complex interactions and potential false discovery, a more comprehensive portrait of genetic determinants in HIV/AIDS will emerge. The carefully assembled phenotype data and specimen repository will also provide a solid infrastructure for further genetic/genomic research at the epidemiologic level and for collaborations with basic scientists aimed at probing the functional correlations of well-documented immunogenetic relationships. PROJECT NARRATIVE This genetic epidemiologic research on variants in key human immune response genes will help explain why individuals differ so widely in the ease with which they become infected with HIV and the rate at which they progress to disease. The knowledge is most directly relevant to the health of African populations. It will also translate into guidance for biomedical scientists who are grappling with the development of HIV vaccines and potential population differences in response to them, pursuing strategies for modulation molecules involved in viral entry into cells, and designing and analyzing intervention trials.

描述（由申请人提供）：人类遗传多态性影响HIV-1感染的发生和演变。艾滋病研究办公室2008财政年度艾滋病毒相关研究计划的目标包括确定宿主遗传因素，这些因素解释了对感染及其后遗症的高度可变反应。这一提议将为这些反应的关键遗传决定因素提供新的见解。这一新的知识将转化为指导疫苗学家努力与艾滋病毒疫苗的发展和潜在的人口差异，在响应他们，生物技术人员追求免疫调节的辅助受体和配体分子的战略，并为临床医生设计和分析干预试验。遗传决定因素将主要在赞比亚、乌干达和卢旺达的受感染和易感人群中进行研究，其次在欧洲和非洲裔美国人艾滋病毒/艾滋病队列中进行研究。主要工作将集中在一个独特的1400异性恋活跃的非洲夫妇谁是不和谐的HIV-1感染（即，一个伴侣HIV-1阳性，一个阴性）。通过对夫妇的调查，可以观察到两个主机连续感染相关病毒的反应，在前所未有的规模。这种自然实验允许对最初未经治疗的个体的传播和病毒进化的遗传效应进行强有力的假设检验。具体目标是针对对病毒反应至关重要的两个途径中的基因。第一个目标涵盖HLA I类抗原递呈途径（HLA-A、HLA-B和HLA-C）中的基因，以及白细胞受体复合物（LRC）基因家族中的基因，包括自然杀伤细胞途径中的KIR基因和LILRB 1。沿着。第二个目标涵盖HIV-1趋化因子辅助受体及其配体（CCR 2、CCR 5、CCL 3、CCL 3L 1、CCL 4、CCL 4L 1和CCL 5）表达途径中的基因。将考虑相关的新候选基因。公共生物信息学数据库、基因组水平测序服务和最先进的实验室技术将用于检测所选基因座内的多态性。主要结果指标包括暴露的HIV-1阴性伴侣的血清转换时间和感染早期血浆病毒RNA水平。个别非洲群组将支持独立的假设检验，并可从明智的汇总群组数据中得出强有力的推论。分析将强调受体和配体基因产物之间的预测相互作用。将检查多种标志物对结果的同时影响。将对非洲人和跨种族边界的HIV-1亚型的影响进行比较。通过应用程序的创新统计方法，利用单倍型识别，复杂的相互作用和潜在的错误发现，将出现一个更全面的艾滋病毒/艾滋病遗传决定因素的画像。精心组装的表型数据和标本库还将为流行病学水平的进一步遗传/基因组研究以及与基础科学家的合作提供坚实的基础设施，旨在探索有据可查的免疫遗传关系的功能相关性。项目叙述 这项关于关键人类免疫反应基因变异的遗传流行病学研究将有助于解释为什么个体在感染艾滋病毒的难易程度和疾病进展速度方面差异如此之大。这些知识与非洲人口的健康最直接相关。它还将转化为生物医学科学家的指导，这些科学家正在努力开发HIV疫苗和潜在的人群差异，寻求参与病毒进入细胞的调节分子的策略，以及设计和分析干预试验。