Host genetic determinants of HIV-AIDS susceptibility in a VA cohort

VA 队列中 HIV-AIDS 易感性的宿主遗传决定因素

• 批准号: 7908824
• 负责人: Sunil K Ahuja
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908824
• 关键词: 17q12; AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; African American; Age; Aging; Air Force Personnel; Alcohol consumption; Alcohols; Alleles; Anti-Retroviral Agents; Antigen Receptors; Antiviral Agents; Ascaridil; Award; Behavior; Binding; Blood Platelets; CCL3L1 gene; CCR5 gene; CD209 gene; CD4 Positive T Lymphocytes; Candidate Disease Gene; Caring; Cell Adhesion Molecules; Cell Count; Cells; Cellular Immunity; Cessation of life; Chemokine (C-C Motif) Receptor 5; Chromosomes; Clinical; Code; Cohort Studies; Commit; Comorbidity; Complement; Complex; Consent; Copy Number Polymorphism; Cost Sharing; DNA; Data; Data Analyses; Defensins; Dependence; Dependency; Dipeptidyl-Peptidase IV; Discipline; Disease; Disease Progression; Drug usage; Enrollment; Epidemic; Epidemiologic Studies; Epidemiologist; Epidemiology; Equilibrium; Erythrocytes; Evaluation; Event; Evolution; Eye; FCGR3B gene; Failure; Family; Fc Receptor; Funding; Funding Agency; GNB3 gene; GTP-Binding Proteins; Gap Junctions; Generations; Genes; Genetic; Genetic Determinism; Genetic Epistasis; Genetic Variation; Genotype; Goals; Grant; HIV; HIV Infections; HIV Seropositivity; HIV-1; HLA-B Antigens; HLA-C Antigens; Hepatitis B Virus; Hepatitis C virus; Highly Active Antiretroviral Therapy; Hispanic Americans; Immune; Immune response; Immunologics; Immunologist; Immunology; In Vitro; Individual; Infection; Integration Host Factors; Interferons; Interleukin-12; Interleukin-2; Interleukin-7; Intrinsic factor; Investigation; Justice; Knowledge; Lead; Learning; Level of Evidence; Life; Life Cycle Stages; Ligands; Liver diseases; Mannose Binding Lectin; Mannose-Binding Lectins; Manuscripts; Mediating; Medical center; Messenger RNA; Microbe; Mutation; N-terminal; National Institute on Alcohol Abuse and Alcoholism; Natural History; Nature; Observational Study; Outcome; Pathogenesis; Pathway interactions; Patients; Perinatal; Phenotype; Play; Population; Predisposition; Prevalence; Process; Production; Public Health; RNA Interference; Recovery; Relative (related person); Research; Research Design; Research Infrastructure; Resources; Risk; Role; Science; Scientist; Serine Protease; Services; Signal Transduction; Site; Source; Specimen; Surface; System; T-Lymphocyte; TSG101 gene; Testing; Time; Transcript; Transducers; Translating; United States National Institutes of Health; Universities; Vaccines; Validation; Variant; Veterans; Vial device; Viral; Viral Load result; Work; antiretroviral therapy; apolipoprotein E-4; base; bench to bedside; biobank; chemokine; chemokine receptor; clinical care; clinically relevant; cohort; cytokine; experience; gene interaction; genetic variant; genome wide association study; genome-wide; human disease; improved; in vivo; indexing; innovation; insight; interest; medical schools; member; multidisciplinary; novel; promoter; protective effect; public health relevance; racial and ethnic; receptor; repository; response; skills; success; therapy development; tool; transcription factor; translational study; transmission process; vaccine efficacy

DESCRIPTION (provided by applicant): There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility during untreated HIV infection and immune recovery during highly active antiretroviral therapy (HAART). We will use state-of-the-art powerful genetic and statistical tools and targeted candidate gene approaches to identify genetic factors that influence HIV-AIDS susceptibility as well as immune recovery during highly active antiretroviral therapy (HAART) in a large cohort of adults from the VA, namely VA Aging Cohort Study (VACS). These studies will thus (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis and immune recovery during HAART in vivo; (b) determine the relative contribution to these determinants to the HIV-1 epidemic at the population level; (c) translate these findings to real life practical issues such as improved clinical care of patients via genetic-based prognostication of AIDS as well as immune recovery during HAART; and (d) the influence of alcohol and age in immune depletion/recovery. In the current application we will test the overall hypothesis that (I) expression of members of the CD4 - CD4 ligand - CCR5 - CCR5 ligand nexus, including relevant transducers of coreceptor signals, will alter HIV/AIDS susceptibility and immune recovery during HAART (aim #1); (II) expression of and interaction between selected candidate genes that influence innate and adaptive immune responses will alter HIV-AIDS susceptibility and immune recovery during HAART (aim #2). These include genes (i) at the MHC and KIR locus; (ii) encoding cellular intrinsic factors (TRIM5 and Apobec3 family); (iii) involved in the HIV life cycle such as PPIA and TSG101; (iv) identified as HIV dependency factors (HDF), and (iv) Copy Number Variation (CNV) at the chemokine gene-rich locus on chromosome 17q12, complement components (C4A and C4B), Fc receptors (FCGR3), and defensins. Thus, this proposal seeks approval for the use of specimens at VA Central biorepository to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility and immune recovery during HAART by amalgamating the unique skills and resources of the research teams at the VA Center for AIDS and HIV Infection at San Antonio, TX (PI: Dr Ahuja) and Yale University School of Medicine, New Haven, CT (PI: Dr Justice). PUBLIC HEALTH RELEVANCE: The studies proposed will provide new insights into the host factors that influence susceptibility to HIV and AIDS, and these findings could provide new ways to develop therapies and vaccines.

描述（由申请人提供）： 越来越多的证据表明，在未经治疗的艾滋病毒感染期间，以及在高效抗逆转录病毒治疗（HAART）期间免疫恢复期间，个体的宿主基因构成是艾滋病毒/艾滋病易感性的重要决定因素。我们将使用最先进的强大遗传和统计工具以及有针对性的候选基因方法来识别影响艾滋病易感性的遗传因素以及在高活性抗逆转录病毒治疗（HAART）期间对来自一大批成年人的免疫恢复。 VA，即VA老龄队列研究（VACS）。因此，这些研究将 (a) 揭示在体内 HAART 期间影响 HIV-1 发病机制和免疫恢复的复杂宿主基因-基因相互作用； (b) 确定这些决定因素对人口层面的 HIV-1 流行的相对贡献； (c) 将这些发现转化为现实生活中的实际问题，例如通过基于艾滋病的基因预测以及HAART期间的免疫恢复来改善患者的临床护理； (d) 酒精和年龄对免疫耗竭/恢复的影响。在当前的应用中，我们将测试总体假设：(I) CD4 - CD4 配体 - CCR5 - CCR5 配体连接成员的表达，包括相关的辅助受体信号转导器，将改变 HAART 期间的 HIV/AIDS 易感性和免疫恢复（目标#1); (II)影响先天性和适应性免疫反应的选定候选基因的表达和相互作用将改变HAART期间的HIV-AIDS易感性和免疫恢复（目标#2）。这些包括 (i) MHC 和 KIR 位点的基因； (ii) 编码细胞内在因子（TRIM5 和 Apobec3 家族）； (iii) 参与HIV生命周期，例如PPIA和TSG101； (iv) 鉴定为 HIV 依赖因子 (HDF)，以及 (iv) 染色体 17q12 上趋化因子基因丰富位点的拷贝数变异 (CNV)、补体成分（C4A 和 C4B）、Fc 受体 (FCGR3) 和防御素。因此，本提案寻求批准使用 VA 中心生物样本库的标本来支持一项合作研究，通过合并 VA 中心研究团队的独特技能和资源，探索 HAART 期间 HIV/艾滋病易感性和免疫恢复的遗传机制德克萨斯州圣安东尼奥市（PI：Ahuja 博士）和康涅狄格州纽黑文市耶鲁大学医学院（PI：Justice 博士）的艾滋病和 HIV 感染研究中心。 公共卫生相关性： 拟议的研究将为影响艾滋病毒和艾滋病易感性的宿主因素提供新的见解，这些发现可以为开发疗法和疫苗提供新方法。