Mitochondria And Metabolic Complications Of HIV

HIV 的线粒体和代谢并发症

• 批准号: 6947701
• 负责人: PABLO TEBAS
• 金额: $ 18.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947701
• 关键词: HIV infections; RNA; adipose tissue; antiAIDS agent; blood chemistry; blood tests; combination chemotherapy; disease /disorder etiology; drug adverse effect; human immunodeficiency virus 1; human subject; insulin sensitivity /resistance; lipid metabolism; lipodystrophy; medical complication; mitochondrial DNA; mitochondrial disease /disorder; reverse transcriptase inhibitors; stavudine

DESCRIPTION (provided by applicant): Lipodystrophy associated with HIV infection is very frequent. It affects at least 50% of HIV-1-infected adults receiving antiretroviral therapy (ART) and can be stigmatizing leading to suboptimal adherence to antiretroviral treatment and subsequent clinical and virologic failure. The pathogenesis of this complication of HIV and its treatment is not completely understood. Clinical evidence suggests that specific nucleoside analogue reverse transcriptase inhibitors (particularly d4T and AZT) are associated with peripheral adipose tissue wasting, which may result from mitochondria! toxicity. Mitochondrial toxicity might be also be a contributor to other metabolic complications seen in patients treated for HIV. There has been considerable interest in using mitochondrial DNA measurements in PBMCs as predictors of nucleoside associated toxicity. So far reports have been conflicting because the studies have been underpowered and they lack of longitudinal objective assessments of body composition and other metabolic parameters. The goals of this proposal are: 1. To evaluate longitudinally the peripheral blood mononuclear cell (PBMC) mitochondrial DNA copy number across PBMC specimens obtained in several ACTG studies. 2. To evaluate relationships between longitudinal changes in PBMC mitochondrial DNA copy number and measures of insulin resistance, lipids and fat distribution in three ACTG studies. 3. To evaluate if the changes in mitochondrial DNA measured in PBMC during the first 16-24 weeks of therapy can be used as a predictors of which individuals will develop peripheral lipoatrophy. 4. Exploratory Aim. To evaluate relationships between longitudinal changes in PBMC mitochondrial RNA and RNA copy number and measures of insulin resistance, lipids and fat distribution in three ACTG studies. In order to do this we will use a NASBA based assay to measure the mitochondrial DNA and RNA content in PBMCs, and use 2000 specimens collected longitudinally in 3 large ACTG studies.

描述（由申请人提供）：与HIV感染相关的脂肪代谢障碍非常常见。它影响到至少50%接受抗逆转录病毒治疗（ART）的HIV-1感染成人，并可能导致对抗逆转录病毒治疗的依从性不佳以及随后的临床和病毒学失败。艾滋病毒的这种并发症的发病机制及其治疗尚未完全了解。临床证据表明，特定的核苷类似物逆转录酶抑制剂（特别是d4 T和AZT）与外周脂肪组织消耗有关，这可能是由线粒体引起的！毒性线粒体毒性也可能是HIV治疗患者中观察到的其他代谢并发症的一个因素。使用PBMC中的线粒体DNA测量作为核苷相关毒性的预测因子已经引起了相当大的兴趣。 到目前为止，报告一直相互矛盾，因为这些研究一直不够有力，他们缺乏对身体成分和其他代谢参数的纵向客观评估。 该提案的目标是： 1.纵向评价几项ACTG研究中获得的PBMC标本的外周血单核细胞（PBMC）线粒体DNA拷贝数。 2.评价三项ACTG研究中PBMC线粒体DNA拷贝数的纵向变化与胰岛素抵抗、脂质和脂肪分布指标之间的关系。 3.评估在治疗的前16-24周期间在PBMC中测量的线粒体DNA的变化是否可用作哪些个体将发展外周脂肪萎缩的预测因子。 4.探索目标。评价三项ACTG研究中PBMC线粒体RNA和RNA拷贝数的纵向变化与胰岛素抵抗、脂质和脂肪分布指标之间的关系。 为了做到这一点，我们将使用基于NASBA的测定来测量PBMC中的线粒体DNA和RNA含量，并使用在3项大型ACTG研究中纵向收集的2000份标本。