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：
10852482
负责人：
Paul Kievit
金额：
$ 128.66万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10852482
关键词：
AIDS diagnosis Acquired Immunodeficiency Syndrome Acute Address Adipose tissue Affect Area Autopsy Biological Markers Biopsy Biopsy Specimen Body Composition Body Weight 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/AIDS Health Histologic Hormone secretion Human Immune Immune response Immunologics Incidence Infection 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 Persons Pharmaceutical Preparations Physiology Plasma Population Pre-Clinical Model Prediabetes syndrome Primates Research Research Design Risk SIV Sampling Science 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.

项目摘要有效的抗逆转录病毒疗法（ART）的出现使数百万的HIV感染患者达到长期缓解和生存到中年和老年。这种增加的生存导致了与艾滋病毒和/或艺术有关的各种合并症，包括代谢疾病，定义癌症和神经认知障碍。特别是关于代谢疾病，与早期艺术体制已被体重增加和脂肪组织改变的发生率增加所取代在较新的ART制剂中，患者中2型糖尿病的功能以及增加的风险。建议的机制包括艾滋病毒引起的肠道完整性的破坏和微生物成分的易位影响组织靶标，例如内脏（尤其是胶质）脂肪组织，以产生慢性状态全身性炎症是代谢功能障碍的有据可查的原因。影响的另一个主要问题拥有艾滋病的人口众多的人是肥胖和糖尿病的全球流行病，也会影响人们在辅助诊断和启动艺术之前。因此，肥胖和糖尿病越来越多艾滋病患者的先前存在的状况，这是我们总体假设的基础肥胖/代谢疾病调节艾滋病毒感染参数和对艺术的反应和加剧不利通过对系统性炎症的添加剂或协同作用来代谢作用。深入调查将现有代谢疾病与艾滋病毒和艺术合并症联系起来的机制需要临床前模型，使研究在人群中不可行。猿猴免疫缺陷病毒（SIV）/SHIV感染的非人类灵长类动物（NHP；恒河猕猴）是研究的主要临床前模型艾滋病毒获取，艺术作用和疫苗开发。 NHP也是理想的实验系统对先前存在的肥胖症的研究表现出对西方饮食的肥胖反应，反映人类的消费模式，因此是人类饮食引起的固有转化模型肥胖和代谢功能障碍。我们建议将这两个独特的NHP模型合并，以模仿人口中的事务，并通过追求以下特定目标来解决我们的假设。特定目的1。在SIV挑战期间确定瘦和肥胖受试者中的病毒和免疫学参数和随后的艺术。特定目标2。在SIV期间，对精益和肥胖受试者进行全面的全身代谢分析挑战和随后的艺术。特定目标3。确定在SIV感染的瘦肉和肥胖受试者之前和期间的组织特异性差异艺术。