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

• 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
• 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

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.

项目总结