Effect of obesity on HIV pathogenesis, antiretroviral therapy, and metabolic comorbidities

肥胖对 HIV 发病机制、抗逆转录病毒治疗和代谢合并症的影响

基本信息

批准号：
10248477
负责人：
Paul Kievit
金额：
$ 84.1万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248477
关键词：
AIDS diagnosis AIDS/HIV problem Acquired Immunodeficiency Syndrome Acute Address Adipose tissue Affect Area Autopsy Biological Markers Biopsy Biopsy Specimen Body Composition Body mass index Cell Size Cells Chronic Chronic Phase Clinical Data Clinical Research Colon Consumption Development Diabetes Mellitus Disease remission Dose Endocrine Endoscopic Biopsy Energy Metabolism Evaluation Exhibits Food Energy Formulation Frequencies Functional disorder Glucose Metabolism Disorders Glycosylated hemoglobin A HIV HIV Infections HIV antiretroviral HIV therapy Health Sciences Histologic Hormone secretion Human Immune Immune response Immunologics Incidence Infection Institutes Insulin Resistance Investigation Islets of Langerhans Kinetics Link Lipodystrophy Longitudinal Studies Lymphoid Macaca Macaca mulatta Malignant Neoplasms Medical Metabolic Metabolic Control Metabolic Diseases Metabolic dysfunction Metabolic hormone Mission Modeling Molecular Monitor Monkeys National Institute of Diabetes and Digestive and Kidney Diseases Newly Diagnosed Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Oregon Organ Outcome Pathogenesis Pathology Patients Pattern Pharmaceutical Preparations Physiology Plasma Population Pre-Clinical Model Prediabetes syndrome Primates Research Research Design Risk SIV Sampling Serum Severities Spleen Study models System Testing Thinness Time Tissue Sample Tissues Universities Vaccine Therapy Viral Viral Load result Viral reservoir Viremia Virus Activation Virus Diseases Virus Latency Visceral Weight Gain adipokines antiretroviral therapy base blood glucose regulation cohort comorbidity diet-induced obesity epidemiologic data food consumption gene therapy glucose metabolism glucose tolerance human old age (65+)in vivo insulin tolerance islet lipid mediator lipid metabolism lymph nodes male microbial middle age neurocognitive disorder nonhuman primate obese person obesity risk obesogenic response simian human immunodeficiency virus subcutaneous systemic inflammatory response therapy development tool translational model transmission process vaccine development western diet

项目摘要

PROJECT SUMMARY The advent of effective antiretroviral therapy (ART) has enabled millions of HIV-infected patients to achieve long-term remission and survival to middle and old age. This increased survival has resulted in development of a variety of comorbidities linked to HIV and/or ART, including metabolic disease, AIDS-defining cancers, and neurocognitive disorders. With respect to metabolic disease in particular, the lipodystrophy associated with early ART regimes has been replaced by an increased incidence of weight gain and altered adipose tissue function as well as increased risk for type-2 diabetes in patients on newer ART formulations. Proposed mechanisms include HIV-induced disruption of gut integrity and translocation of microbial components that can affect tissue targets such as visceral (particularly omental) adipose tissue to generate a state of chronic systemic inflammation that is a well-documented cause of metabolic dysfunction. Another major issue affecting the large population of people living with AIDS is the global epidemic of obesity and diabetes that also affects people prior to their AIDS diagnosis and initiation of ART. Thus, obesity and prediabetes are increasingly a pre-existing condition in people living with AIDS, and is the basis for our overall hypothesis that pre-existing obesity/metabolic disease regulates HIV infection parameters and response to ART and exacerbates adverse metabolic effects through additive or synergistic effects on systemic inflammation. The in-depth investigation of the mechanisms that link pre-existing metabolic disease with metabolic comorbidities of HIV and ART requires preclinical models that enable studies not feasible in human populations. Simian immunodeficiency virus (SIV)/SHIV-infected nonhuman primates (NHP; rhesus macaques) are the primary preclinical model for study of HIV acquisition, effects of ART, and vaccine development. NHPs are also the ideal experimental system for the investigation of pre-existing obesity as it exhibits an obesogenic response to a western-style diet that mirrors human consumption patterns and is thus an inherently translational model for human diet-induced obesity and metabolic dysfunction. We propose to merge these two unique NHP models to mimic the state of affairs in the human population and to address our hypothesis through pursuit of the following specific aims. Specific aim 1. Determine viral and immunological parameters in lean and obese subjects during SIV challenge and subsequent ART. Specific aim 2. Perform comprehensive systemic metabolic profiling in lean and obese subjects during SIV challenge and subsequent ART. Specific aim 3. Determine tissue-specific differences in SIV-infected lean and obese subjects before and during ART.

项目概要有效的抗逆转录病毒疗法（ART）的出现使数百万艾滋病毒感染者实现了长期缓解并生存至中老年。这种生存率的提高导致了与 HIV 和/或 ART 相关的各种合并症，包括代谢性疾病、艾滋病定义的癌症，以及神经认知障碍。特别是对于代谢疾病，与脂肪营养不良相关的早期的 ART 方案已被体重增加发生率增加和脂肪组织改变所取代使用新的 ART 制剂的患者的功能以及 2 型糖尿病的风险增加。建议的机制包括 HIV 引起的肠道完整性破坏和微生物成分易位，影响组织目标，例如内脏（特别是网膜）脂肪组织，产生慢性状态全身炎症是代谢功能障碍的一个有据可查的原因。另一个影响的重大问题大量艾滋病患者是肥胖和糖尿病的全球流行病，也影响到在艾滋病诊断和开始抗逆转录病毒疗法之前的人。因此，肥胖和糖尿病前期日益成为一个艾滋病患者原有的状况，这是我们总体假设的基础，即原有的状况肥胖/代谢疾病调节 HIV 感染参数和对 ART 的反应，并加剧不良反应通过对全身炎症的累加或协同作用产生代谢作用。深入调查将先前存在的代谢疾病与 HIV 和 ART 的代谢合并症联系起来的机制需要使研究在人群中不可行的临床前模型。猿猴免疫缺陷病毒 (SIV)/SHIV 感染的非人类灵长类动物（NHP；恒河猴）是主要的临床前研究模型 HIV 感染、ART 的影响和疫苗开发。 NHP 也是理想的实验系统对已有肥胖症的调查，因为它表现出对西式饮食的致胖反应反映了人类的消费模式，因此本质上是人类饮食引起的转化模型肥胖和代谢功能障碍。我们建议合并这两个独特的 NHP 模型来模拟人类事务中的问题，并通过追求以下具体目标来解决我们的假设。具体目标 1. 确定瘦和肥胖受试者在 SIV 攻击期间的病毒和免疫学参数以及随后的艺术。具体目标 2. 在 SIV 期间对瘦人和肥胖受试者进行全面的系统代谢分析挑战和随后的 ART。具体目标 3. 确定感染 SIV 的瘦和肥胖受试者在治疗前和治疗期间的组织特异性差异艺术。