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: 7808862
• 负责人: Richard Alan Kaslow
• 金额: $ 65.58万
• 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/7808862
• 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; Clinical; Collaborations; Complex; Copy Number Polymorphism; Couples; Critical Pathways; Cytotoxic T-Lymphocytes; DNA Sequence; Data; Development; Disease; Epidemiologic Studies; Epidemiology; 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 gene; 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; 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; non-genetic; 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(申请人提供)：人类基因多态影响HIV-1感染的发生和演变。艾滋病研究办公室2008财年艾滋病毒相关研究计划的目标包括确定宿主遗传因素，以解释对感染及其后遗症的高度可变反应。这项拟议的倡议将为这些反应的关键基因决定因素提供新的见解。这一新知识将转化为指导疫苗专家努力应对艾滋病毒疫苗的开发和潜在的人群差异，生物技术专家寻求共受体和配体分子的免疫调节策略，以及临床医生设计和分析干预试验。基因决定因素将主要在赞比亚、乌干达和卢旺达的感染和易感人群中进行研究，其次在欧洲和非裔美国人的艾滋病毒/艾滋病队列中进行研究。主要工作将集中在由1400对异性活跃的非洲夫妇组成的独特的集会，他们对艾滋病毒-1感染存在分歧(即一个伴侣艾滋病毒-1阳性，一个伴侣艾滋病毒-1阴性)。通过对夫妻的调查，可以在前所未有的规模上观察到两个先后感染相关病毒的宿主的反应。这一自然实验允许对最初未治疗的个体中对传播和病毒进化的遗传影响进行强大的假设检验。特定的目标针对对病毒的反应至关重要的两条途径的基因。第一个目标是包括人类白细胞抗原I类递呈途径的基因(包括人类白细胞受体复合体基因家族中的KIR基因和自然杀伤细胞途径中的LILRB1)。第二个目标包括HIV-1趋化因子共受体及其配体(CCR2、CCR5、CCL3、CCL3L1、CCL4、CCL4L1和CCL5)表达途径中的基因。相关的新候选基因将被考虑。将使用公共生物信息学数据库、基因组水平的测序服务和最先进的实验室技术来检测选定基因座的多态。主要的观察指标包括暴露于HIV-1阴性伴侣的血清转换时间和感染早期的血浆病毒RNA水平。单独的非洲队列将支持独立的假设检验，从明智地聚合队列的数据中可以得出强有力的推论。分析将强调受体和配体基因产物之间的预测相互作用。多个标记物对结果的同时影响将被检验。将对非洲人内部和种族边界内的HIV-1亚型的影响进行比较。通过该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，将出现对艾滋病毒/艾滋病遗传决定因素的更全面的描述。精心组合的表型数据和标本储存库还将为流行病学层面的进一步遗传/基因组研究以及与旨在探索有充分记录的免疫遗传关系的功能相关性的基础科学家的合作提供坚实的基础设施。项目叙事 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易感性和疾病进展速度方面存在如此大的差异。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应对艾滋病毒疫苗的开发和潜在的人群差异，寻求参与病毒进入细胞的调制分子的策略，以及设计和分析干预试验。