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

基本信息

批准号：
8112582
负责人：
TODD M HULGAN
金额：
$ 15.13万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8112582
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adherence Adverse effects Animal Model Anti-Retroviral Agents 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 Degenerative Disorder 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

项目摘要

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）：可卡因是艾滋病毒感染者中常见的滥用药物，其用途与较差的临床结局独立相关，包括更快的HIV疾病进展。除了限制对医疗和艾滋病毒治疗的社会心理稳定性的间接影响外，数据还表明可卡因对CD4+和CD8+ T细胞功能的直接影响以及增强的HIV复制，这可能导致加速HIV疾病。可卡因已显示出对多个体外和动物模型系统中细胞的不利影响 - 主要是通过凋亡途径的线粒体诱导。鉴于线粒体介导的凋亡在HIV感染过程中CD4+ T细胞耗竭中的主要作用，我们怀疑可卡因对CD4+ T细胞的不受影响的作用和HIV疾病进展是通过线粒体诱导的凋亡介导的，尽管数据将Cocaine与CD4+ T缺乏CD4+ T的数据联系在一起，但仍缺乏CD4+ T细胞apoptiss。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，抗氧化能力的主要介体，抗氧化能力和诱导凋亡对细胞损伤的响应。线粒体DNA单倍体基于遗传的多态性变异，表示母体血统和人类迁移，并且与退化性和代谢性疾病的风险以及寿命有关。我们的小组致力于了解MTDNA变异在HIV治疗并发症中的相关性，而其他研究者的最新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。拟议的试点研究的目标是通过对可卡因使用对种群和机械水平的CD4+ T细胞的影响进行新的分析，以更好地了解药物使用与改变HIV的进展之间的相互作用，并有助于发病机理，以及如何通过mtDNA变异调节这些作用。我们将通过两个研究目的实现这些目标，该目标将利用现有数据和标本的次级分析：1）确定MTDNA变异与可卡因诱导的对CD4+和CD8+ T细胞激活的影响和可卡因诱导的影响，来自HIV感染者的外周血细胞中的伴随。 2）确定在HIV感染的可卡因使用者和非用户中，mtDNA变异与抗逆转录病毒疗法CD4+ T细胞水平之间的关联。公共卫生相关性：拟议研究的目的是探索人类线粒体基因的变异在使用可卡因的HIV感染者中看到的更严重的免疫功能障碍和更快的疾病进展。这些试验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，它们将为未来的临床试验提供旨在改善HIV感染者预后的临床试验。