Mitochondrial Genomics and Effects of Cocaine on T cells during HIV-Infection

HIV 感染期间线粒体基因组学和可卡因对 T 细胞的影响

• 批准号: 7931761
• 负责人: TODD M HULGAN
• 金额: $ 15.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931761
• 关键词: Acquired Immunodeficiency Syndrome; Adherence; Adverse effects; Animal Model; Antioxidants; Apoptosis; Apoptotic; Area; Award; Biological Models; Blood Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Caring; Caspase; Cell Count; Cell physiology; Cells; Clinic; Clinical; Clinical Data; Clinical Trials Design; Cocaine; Cocaine Users; DNA; DNA Sequence; Data; Disease; Disease Progression; Drug abuse; Drug usage; European; Exhibits; Feasibility Studies; Flow Cytometry; Future; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; HIV; HIV Infections; Haplogroup; Hepatic; Human; Immune System Diseases; Immune system; Immunophenotyping; In Vitro; Individual; Induction of Apoptosis; Inherited; Investigation; Link; Longevity; Mediating; Mediator of activation protein; Medical; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Myocardial; National Institute of Drug Abuse; Neurons; Outcome; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Persons; Pilot Projects; Play; Population; Predisposition; Protein Subunits; Recording of previous events; Recovery; Research; Research Personnel; Risk; Role; Science; Specimen; Subgroup; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Variant; antiretroviral therapy; base; career; cocaine exposure; cocaine use; cohort; cytochrome c; disorder risk; drug of abuse; human migration; improved; novel; programs; psychosocial; public health relevance; response

DESCRIPTION (provided by applicant): Cocaine is a common drug of abuse among HIV-infected persons, and its use has been independently associated with poorer clinical outcomes, including more rapid HIV disease progression. In addition to indirect effects on psychosocial stability that limit adherence to medical care and HIV treatments, data also suggest direct effects of cocaine on CD4+ and CD8+ T cell function and enhanced HIV replication that may contribute to accelerated HIV disease. Cocaine has been shown to have adverse effects on cells in multiple in vitro and animal model systems- primarily through mitochondrial induction of the apoptotic pathway. Given the primary role of mitochondria-mediated apoptosis in CD4+ T cell depletion during HIV-infection, we suspect that the untoward effects of cocaine on CD4+ T cells and HIV disease progression are mediated by mitochondria- induced apoptosis, though data directly linking cocaine exposure to enhanced CD4+ T cell apoptosis are lacking. Mitochondrial DNA (mtDNA) is present in each mitochondrion, encodes protein subunits required for cellular oxidative phosphorylation, and is a primary mediator of oxidative stress, antioxidant capacity, and induction of apoptosis in response to cellular damage. Mitochondrial DNA haplogroups are based on inherited polymorphic variation, denote maternal ancestry and human migrations, and have been associated with risk of degenerative and metabolic diseases, and longevity. Our group has devoted considerable effort to understanding the relevance of mtDNA variation in HIV treatment complications, and a recent study by other investigators identified associations between haplogroups and HIV disease progression in cohorts of persons of European descent. The goals of the proposed pilot studies are to better understand interactions between drug use and altered HIV progression and AIDS pathogenesis through novel analyses of the effects of cocaine use on CD4+ T cells at both the population and mechanistic level, and how these effects are modulated by mtDNA variation. We will attain these goals through two study aims that will utilize secondary analysis of existing data and specimens: 1) To identify associations between mtDNA variation and cocaine-induced effects on CD4+ and CD8+ T cell activation and apoptosis in peripheral blood cells from HIV-infected persons; and 2) To identify associations between mtDNA variation and pre- and post-antiretroviral therapy CD4+ T cell levels in HIV-infected cocaine users and non-users. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to explore the role that variation in human mitochondrial genes may play in the more severe immune dysfunction and faster disease progression seen in HIV-infected persons who use cocaine. Results from these pilot studies will improve our understanding of the relationships between mitochondrial genes, cocaine, and the immune system, and they will inform future clinical trials designed to improve outcomes of HIV-infected persons.

描述（由申请人提供）：可卡因是 HIV 感染者中常见的滥用药物，其使用与较差的临床结果独立相关，包括更快的 HIV 疾病进展。除了对心理社会稳定性的间接影响限制了对医疗保健和艾滋病毒治疗的依从性之外，数据还表明可卡因对 CD4+ 和 CD8+ T 细胞功能以及增强艾滋病毒复制的直接影响可能会加速艾滋病毒疾病的发展。可卡因已被证明对多种体外和动物模型系统中的细胞产生不利影响——主要是通过线粒体诱导细胞凋亡途径。鉴于线粒体介导的细胞凋亡在 HIV 感染期间 CD4+ T 细胞耗竭中的主要作用，我们怀疑可卡因对 CD4+ T 细胞和 HIV 疾病进展的不良影响是由线粒体诱导的细胞凋亡介导的，尽管缺乏将可卡因暴露与增强的 CD4+ T 细胞凋亡直接联系起来的数据。线粒体 DNA (mtDNA) 存在于每个线粒体中，编码细胞氧化磷酸化所需的蛋白质亚基，并且是氧化应激、抗氧化能力和诱导细胞损伤响应细胞凋亡的主要介质。线粒体 DNA 单倍群基于​​遗传多态性变异，表示母系血统和人类迁徙，并与退行性和代谢性疾病以及长寿的风险相关。我们的小组投入了大量精力来了解 mtDNA 变异与 HIV 治疗并发症的相关性，其他研究人员最近的一项研究确定了欧洲血统人群中单倍群与 HIV 疾病进展之间的关联。拟议试点研究的目标是通过对可卡因使用在群体和机制水平上对 CD4+ T 细胞的影响以及这些影响如何通过 mtDNA 变异进行调节的新分析，更好地了解药物使用与改变的 HIV 进展和艾滋病发病机制之间的相互作用。我们将通过两个研究目标来实现这些目标，这些目标将利用对现有数据和样本的二次分析：1) 确定 mtDNA 变异与可卡因诱导的对 HIV 感染者外周血细胞 CD4+ 和 CD8+ T 细胞活化和凋亡的影响之间的关联； 2) 确定感染 HIV 的可卡因使用者和非使用者的 mtDNA 变异与抗逆转录病毒治疗前后 CD4+ T 细胞水平之间的关联。 公共健康相关性：拟议研究的目的是探索人类线粒体基因变异在使用可卡因的艾滋病毒感染者中出现的更严重的免疫功能障碍和更快的疾病进展中可能发挥的作用。这些试点研究的结果将增进我们对线粒体基因、可卡因和免疫系统之间关系的理解，并将为未来旨在改善艾滋病毒感染者预后的临床试验提供信息。