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治疗方案，患有围产期获得的人类免疫缺陷病毒（HIV）感染的儿童现在已经过着成年。这种疗法在延长寿命中的成功与新兴和渐进的长期并发症相结合，包括代谢异常，例如胰岛素抵抗，糖尿病和身体组成变化。随着儿童年龄的年龄，围产期获得的HIV感染的影响，正在通过衡量身体成分，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。我们先前已经报道了该队列中胰岛素抵抗的高流行。线粒体功能障碍是由抗逆转录病毒疗法诱导的或慢性病毒感染引起的，它已被我们推测为HIV感染成人的代谢功能障碍的一种机制。 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功能障碍； 2。在4年内纵向，以确定Oxphos蛋白/酶活性的年变化以及多乳酸化的发生率和分辨率，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，线粒体RNA转录本和线粒体氧化应激的艾滋病毒感染儿童的线粒体DNA拷贝，具有最高的胰岛素抑制作用和最低的胰岛素抑制性，通过rya蛋白的抗性，通过胰岛素抵抗最高。我们假设抗逆转录病毒药物和HIV的线粒体毒性主要是由线粒体RNA和Oxphos蛋白/酶活性水平的改变驱动的，这又会增加线粒体活性氧气和乳酸水平，从而导致胰岛素抵抗和脂肪症。我们进一步假设外周血单核细胞（PBMC）或颊细胞（脸颊拭子）中的Oxphos蛋白/酶活性水平将与代谢疾病的程度相关。如果这些假设得到验证，那么在理解小儿艾滋病毒/艾滋病代谢异常的发病机理时，人类健康的相关性将有很大的相关性。此外，PBMCS或颊细胞的Oxphos蛋白/酶活性可以用作预先监测受试者的工具，以确保线粒体代谢功能障碍的风险。 公共卫生相关性：感染HIV的儿童有糖尿病前，糖尿病和脂肪变化的风险，最终将导致心脏病和早期死亡的风险增加。我们正在尝试了解与糖尿病前，糖尿病和脂肪变化相关的机制和风险因素。这应该有助于将来的干预措施最大程度地减少感染HIV感染的儿童的这些疾病。