Mitochondrial Determinants of Metabolic Disease in HIV-Infected Children

描述（由申请人提供）：由于有效的抗逆转录病毒治疗，患有围产期获得性人类免疫缺陷病毒（HIV）感染的儿童现在可以很好地活到成年。这种疗法在延长生命方面取得的成功与新出现的和进行性的长期并发症相结合，包括胰岛素抵抗、糖尿病和身体成分变化等代谢异常。随着儿童年龄增长到青春期，围产期获得性艾滋病毒感染的影响，并通过测量身体成分、青春期阶段、胰岛素抵抗和血脂异常的变化来评估营养、生长和代谢。我们以前曾报道在这个队列中胰岛素抵抗的患病率很高。线粒体功能障碍，无论是由抗逆转录病毒治疗或慢性病毒感染，已被我们假设为一个机制，代谢功能障碍的艾滋病毒感染的成年人。该提案的目标是1。比较PHACS中300名HIV（+）儿童和100名HIV（-）儿童以及HIV（+）儿童的线粒体功能[氧化磷酸化（OXPHOS）蛋白/酶活性和乳酸水平]，以确定与线粒体功能障碍相关的临床特征（代谢、年龄、性别、青春期、病毒载量、抗逆转录病毒治疗）; 2.纵向超过4年，以确定OXPHOS蛋白/酶活性的年度变化和高乳酸血症的发生率和消退，以及这些变化的临床相关性;和3.通过定量和比较每个细胞的线粒体DNA拷贝数，线粒体RNA转录物，和线粒体氧化应激在HIV感染的儿童与胰岛素抵抗的最高和最低的三分位数测量HOMA-IR。我们假设，抗逆转录病毒药物和HIV本身的线粒体毒性主要是由线粒体RNA和OXPHOS蛋白的改变驱动。酶活性水平，这反过来又增加线粒体活性氧应激和乳酸水平，导致胰岛素抵抗和脂肪代谢障碍。我们进一步假设外周血单核细胞（PBMC）或颊细胞（颊拭子）中OXPHOS蛋白/酶活性的水平将与代谢疾病的程度相关。如果这些假设得到验证，将有显着的人类健康的相关性在儿童HIV/AIDS代谢异常的发病机制的理解。此外，PBMC或口腔细胞的OXPHOS蛋白/酶活性可用作预先监测受试者线粒体代谢功能障碍风险的工具。

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.