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

描述(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，包括更快的艾滋病毒疾病进展。除了对心理社会稳定的间接影响限制了对医疗保健和艾滋病毒治疗的坚持，数据还表明可卡因对CD4+和CD8+T细胞功能的直接影响，以及可能导致加速艾滋病毒疾病的艾滋病毒复制。可卡因已被证明在多种体外和动物模型系统中对细胞有不利影响-主要是通过线粒体诱导凋亡途径。鉴于线粒体介导的细胞凋亡在HIV感染过程中CD4+T细胞耗尽中的主要作用，我们怀疑可卡因对CD4+T细胞的不良影响和HIV疾病的进展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的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、抗氧化能力和诱导细胞损伤后细胞凋亡的主要介质。线粒体DNA单倍群基于遗传的多态变异，代表母系祖先和人类迁徙，并与退行性和代谢性疾病的风险和长寿有关。我们小组花了相当大的努力来了解线粒体DNA变异与艾滋病毒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单倍组与欧洲血统人群中艾滋病毒疾病进展之间的联系。拟议的初步研究的目标是通过在人群和机制水平上对可卡因对CD4+T细胞的影响以及线粒体DNA变异如何调节这些影响的新分析，更好地了解药物使用和改变的艾滋病毒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样本的二次分析来实现这些目标：1)确定线粒体DNA变异与可卡因对艾滋病毒感染者外周血细胞中CD4+和CD8+T细胞激活和凋亡的影响之间的关联；以及2)确定线粒体DNA变异与艾滋病毒感染者和非吸毒者抗逆转录病毒治疗前后CD4+T细胞水平之间的关联。 公共卫生相关性：拟议研究的目标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。这些初步研究的结果将提高我们对线粒体基因、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参考。

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.