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 感染相关的脂肪营养不良非常常见。它影响至少 50% 接受抗逆转录病毒治疗 (ART) 的 HIV-1 感染成年人，并可能导致耻辱，导致抗逆转录病毒治疗依从性不佳以及随后的临床和病毒学失败。这种艾滋病毒并发症的发病机制及其治疗尚不完全清楚。临床证据表明，特定的核苷类似物逆转录酶抑制剂（特别是 d4T 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艾滋病毒治疗患者出现的其他代谢并发症的一个原因。人们对使用 PBMC 中的线粒体 DNA 测量作为核苷相关毒性的预测因子产生了很大的兴趣。 到目前为止，报告一直相互矛盾，因为这些研究动力不足，而且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. 纵向评估在多项 ACTG 研究中获得的 PBMC 样本中的外周血单核细胞 (PBMC) 线粒体 DNA 拷贝数。 2. 评估三项 ACTG 研究中 PBMC 线粒体 DNA 拷贝数的纵向变化与胰岛素抵抗、血脂和脂肪分布测量值之间的关系。 3. 评估治疗前 16-24 周期间 PBMC 中测量的线粒体 DNA 的变化是否可以用作哪些个体将出现外周脂肪萎缩的预测因子。 4.探索性目标。评估三项 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、血脂和脂肪分布测量值之间的关系。 为了做到这一点，我们将使用基于 NASBA 的测定法来测量 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 个样本。