Host Genetic Determinants of HIV Pathogenesis

HIV发病机制的宿主遗传决定因素

• 批准号: 8119291
• 负责人: Sunil K Ahuja
• 金额: $ 70.56万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119291
• 关键词: AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; Antibodies; Attention; Behavior; Biology; CCL3L1 gene; CCL4 gene; CCR5 gene; CD8B1 gene; Candidate Disease Gene; Caring; Cells; Chromosomes, Human, Pair 12; Clinic; Clinical; Communities; Complement; Complementary DNA; Complex; Coupled; Cytotoxic T-Lymphocytes; Defensins; Development; Disease; Dose; Epidemic; Epidemiology; Evaluation; Event; Evolution; Figs - dietary; Funding; GTP-Binding Proteins; Gap Junctions; Gene Amplification; Gene Dosage; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genotype; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Haplotypes; Highly Active Antiretroviral Therapy; Homeostasis; Human; Immune; Immune response; Immunity; Immunogenetics; Immunology; Individual; Infection; Influentials; Integration Host Factors; Interferons; Interleukin-15; Interleukin-2; Interleukin-7; Investigation; Knowledge; Life; Ligands; Light; Link; Maintenance; Mediating; Modeling; Molecular Biology; Molecular Genetics; Mourning; Nature; Parents; Pathogenesis; Patients; Philosophy; Play; Population; Population Genetics; Predisposition; Process; Protein Isoforms; Public Health; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research; Research Ethics Committees; Resources; Risk; Role; Running; Signal Transduction; Specimen; Study Section; System; T-Lymphocyte; Testing; Time; Transducers; Translating; Translations; Utah; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Viral Physiology; Virus; Work; Writing; alpha-Defensins; arm; base; biological systems; chemokine; clinical care; cohort; cytokine; design; essays; expedited review; forging; forkhead protein; gaze; gene interaction; genetic epidemiology; improved; in vivo; insight; member; response; skills; statistics; tool; transcription factor; vaccine development; vaccine evaluation; virology

There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility. We have integrated genetics, immunology, and evolution, and used them as powerful tools to (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis 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 geneticbased prognostication of AIDS as well as design and evaluation of vaccine trials; and (d) shed light on the immune correlates of a protective anti-HIV response in vivo that can be modeled for rational vaccine design. 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 (aim #1); (II) expression of candidate genes that influence T cell dynamics and regulation will alter HIV/AIDS susceptibility (aim #2); and (III) HIV/AIDS susceptibility is linked to the gene dose of alpha-defensins (aim #3). In aim #4, we will explore means to place host genetics in a broader framework, and will determine their influence on AIDS prognostication, T cell dynamics and other public health aspects of the epidemic. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA), epidemiology/virology/statistics (WHMC), population genetics (Utah) and immunolog/virology (Vanderbilt). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46.110, and is a continuation of an existing approved IRB proposal.

越来越多的证据表明，个体的宿主基因组成是强大的决定因素 艾滋病毒/艾滋病敏感性。我们已经整合了遗传学，免疫学和进化，并将其用作 （A）发现影响HIV-1发病机理的复杂宿主基因相互作用的强大工具； （b）确定对这些决定因素在人群水平上对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，例如通过基于遗传的患者改善患者的临床护理 艾滋病的预后以及疫苗试验的设计和评估； （d）在 可以为理性疫苗设计建模的保护性抗HIV反应的免疫相关性。 在当前应用中，我们将测试总体假设，即（i）CD4 -CD4成员的表达 配体-CCR5 -CCR5配体Nexus（包括相关的croecector信号换能器）将改变 艾滋病毒/艾滋病敏感性（AIM＃1）； （ii）影响T细胞动力学和 法规将改变艾滋病毒/艾滋病敏感性（AIM＃2）； （iii）HIV/AIDS敏感性与该基因有关 α-防御素的剂量（AIM＃3）。在AIM＃4中，我们将探索将寄主遗传学放置在更广泛的 框架，并将确定它们对艾滋病预测，T细胞动态和其他公众的影响 流行病的健康方面。因此，该提案寻求资金支持协作研究以探索 通过合并独特的技能和资源，艾滋病毒/艾滋病敏感的遗传机制 在两个不同的研究小组，即遗传学（UTHSCSA），流行病学/病毒学/统计学（WHMC）， 人口遗传学（犹他州）和免疫/病毒学（范德比尔特）。这项研究将利用现有的， 匿名，未连接的人类标本。 IRB批准了这些标本的遗传研究 以前在45 CFR 46.110授权的快速审查中获得，并且是 现有批准的IRB提案。