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

描述（由申请人提供）：可卡因是艾滋病毒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，包括更迅速的艾滋病毒疾病进展。除了对社会心理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外，数据还表明，可卡因对CD4+和CD8+ T细胞功能的直接影响以及对艾滋病毒复制的增强可能导致艾滋病毒疾病的加速。在多种体外实验和动物模型系统中，可卡因已被证明对细胞有不良影响，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，尽管缺乏直接将可卡因暴露与增强CD4+ T细胞凋亡联系起来的数据。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，是氧化应激、抗氧化能力和细胞损伤诱导凋亡的主要介质。线粒体DNA单倍群以遗传多态性变异为基础，表示母系祖先和人类迁徙，并与退行性疾病和代谢疾病的风险以及长寿有关。我们的团队已经投入了相当大的努力来理解mtDNA变异与HIV治疗并发症的相关性，其他研究者最近的一项研究发现了欧洲血统人群中单倍群与HIV疾病进展之间的关联。拟议的试点研究的目标是通过在群体和机制水平上分析可卡因使用对CD4+ T细胞的影响，以及这些影响如何被mtDNA变异调节，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。我们将通过对现有数据和标本进行二次分析的两个研究目的来实现这些目标：1)确定mtDNA变异与可卡因诱导的hiv感染者外周血中CD4+和CD8+ T细胞活化和凋亡之间的关联；2)确定感染艾滋病毒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细胞水平之间的关系。

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.