Mitochondria And Metabolic Complications Of HIV

描述（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。这种艾滋病并发症的发病机制及其治疗方法尚不完全清楚。临床证据表明，特异性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在接受HIV治疗的患者中看到的其他代谢并发症的一个因素。在pbmc中使用线粒体DNA测量作为核苷相关毒性的预测指标已经引起了相当大的兴趣。到目前为止，报告一直存在矛盾，因为研究力度不足，而且缺乏对身体成分和其他代谢参数的纵向客观评估。本建议的目标是：

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.