Mitochondrial Determinants of Metabolic Disease in HIV-Infected Children

HIV 感染儿童代谢疾病的线粒体决定因素

• 批准号: 8150961
• 负责人: MARIANA GERSCHENSON
• 金额: $ 50.92万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150961
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adolescence; Adult; Age; Anti-Retroviral Agents; Body Composition; CD4 Lymphocyte Count; Cells; Cessation of life; Characteristics; Cheek structure; Child; Childhood; Chronic; Clinical; Cohort Studies; Coupled; Cross-Sectional Studies; Diabetes Mellitus; Disease; Dyslipidemias; Enrollment; Etiology; Fatty acid glycerol esters; Functional disorder; Future; Growth; HIV; Health; High Prevalence; Hip region structure; Human; Immunologic Deficiency Syndromes; Incidence; Insulin Resistance; Intervention; Lead; Life; Lipodystrophy; Measures; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial RNA; Monitor; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathogenesis; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Prediabetes syndrome; Prevalence; Proteins; Puberty; Regimen; Reporting; Resolution; Risk; Risk Factors; Severity of illness; Staging; Stress; Swab; Toxic effect; Transcript; Triceps Brachii Muscle; Venous; Viral Load result; Virus Diseases; antiretroviral therapy; cohort; enzyme activity; heart disease risk; mitochondrial dysfunction; nutrition; pediatric AIDS; pediatric human immunodeficiency virus; prospective; public health relevance; sex; success; tool

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.

描述（由申请人提供）：由于有效的抗逆转录病毒疗法，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生活到成年期。这种疗法在延长寿命方面的成功伴随着新出现和进行性的长期并发症，包括胰岛素抵抗、糖尿病和身体成分变化等代谢异常。随着儿童进入青春期，围产期获得艾滋病毒感染的影响正在通过测量身体成分、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。我们之前曾报道过该队列中胰岛素抵抗的患病率很高。我们假设线粒体功能障碍是由抗逆转录病毒治疗或慢性病毒感染引起的，是艾滋病毒感染成人代谢功能障碍的机制。本提案的目的是 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） 功能障碍； 2. 纵向超过 4 年，确定 OXPHOS 蛋白/酶活性的年度变化和高乳酸血症的发生率和缓解情况，以及这些变化的临床相关性； 3. 通过定量和比较 HIV 感染儿童中每个细胞的线粒体 DNA 拷贝、线粒体 RNA 转录本和线粒体氧化应激（HOMA-IR 测量的胰岛素抵抗最高与最低三分位），描绘线粒体功能障碍的机制。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/酶活性水平的改变引起的，这反过来又增加了线粒体活性氧应激和乳酸水平，导致胰岛素抵抗和脂肪营养不良。我们进一步假设外周血单核细胞 (PBMC) 或口腔细胞（脸颊拭子）中 OXPHOS 蛋白/酶活性的水平与代谢疾病的程度相关。如果这些假设得到验证，那么了解儿科艾滋病毒/艾滋病代谢异常的发病机制将具有重大的人类健康相关性。此外，PBMC 或口腔细胞的 OXPHOS 蛋白/酶活性可以作为预先监测受试者线粒体代谢功能障碍风险的工具。 公共卫生相关性：感染艾滋病毒的儿童面临糖尿病前期、糖尿病和脂肪变化的风险，最终导致心脏病和过早死亡的风险增加。我们正在尝试了解与糖尿病前期、糖尿病和脂肪变化相关的机制和危险因素。这应该有助于未来的干预措施，最大限度地减少艾滋病毒感染儿童的这些疾病。