Mitochondrial Determinants of Metabolic Disease in HIV-Infected Children

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DESCRIPTION (provided by applicant): Children with perinatally-acquired Human Immunodeficiency Virus (HIV) infection are now living well into adulthood owing to effective antiretroviral regimens. The success of this therapy in prolonging life has been coupled with emerging and progressive longer-term complications, including metabolic abnormalities such as insulin resistance, diabetes mellitus, and body composition changes. The the effects of perinatally- acquired HIV infection as children age into adolescence and is evaluating nutrition, growth and metabolism by measuring changes in body composition, pubertal stage, insulin resistance, and dyslipidemia. We have previously reported a high prevalence of insulin resistance in this cohort. Mitochondrial dysfunction, either induced by antiretroviral therapy or chronic viral infection, has been a postulated by us as a mechanism for metabolic dysfunction in HIV infected adults. The objectives of this proposal are to 1. compare mitochondrial function [oxidative phosphorylation (OXPHOS) protein/enzyme activities and lactate levels] of 300 HIV (+) children and 100 HIV (-) in PHACS and among the HIV (+) children, to determine clinical characteristics (metabolic, age, sex, puberty, viral load, antiretroviral therapy) associated with mitochondrial dysfunction; 2. longitudinally over 4 years, to determine the annual change in OXPHOS protein/enzyme activities and the incidence and resolution of hyperlactemia, as well as the clinical correlates of these changes; and 3. delineate mechanisms of mitochondrial dysfunction by quantitating and comparing mitochondrial DNA copies per cell, mitochondrial RNA transcripts, and mitochondrial oxidative stress in the HIV-infected children with the highest versus the lowest tertile of insulin resistance as measured by HOMA-IR. We hypothesize that the mitochondrial toxicities of antiretroviral medications and HIV itself are driven primarily by alterations in mitochondrial RNA and OXPHOS protein/enzyme activity levels, which in turn increase mitochondrial reactive oxygen stress and lactate levels, resulting in insulin resistance and lipodystrophy. We further hypothesize that levels of OXPHOS proteins/enzyme activities in peripheral blood mononuclear cells (PBMCs) or buccal cells (cheek swabs) will correlate with the degree of the metabolic disease. Should these hypotheses be verified, there would be significant human health relevance in the understanding of the pathogenesis of metabolic abnormalities in pediatric HIV/AIDS. Additionally, PBMCs' or buccal cells' OXPHOS protein/enzyme activities may serve as tools to monitor subjects preemptively for risk of mitochondrial metabolic dysfunction. PUBLIC HEALTH RELEVANCE: HIV-infected children are at risk for pre-diabetes, diabetes, and fat changes that will eventually lead to an increased risk for heart disease and early death. We are trying to understand the mechanisms and risk factors associated with pre-diabetes, diabetes, and fat changes. This should help future interventions to minimize these diseases in HIV-infected children.