Mitochondria And Metabolic Complications Of HIV

University Of Pennsylvania, Philadelphia PA

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Abstract

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.