Investigating Cellular Immunometabolic Mechanisms Underlying HIV-Related Cardiovascular Disease Risk

研究 HIV 相关心血管疾病风险背后的细胞免疫代谢机制

• 批准号: 10326950
• 负责人: Michael Jay Corley
• 金额: $ 61.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326950
• 关键词: Advanced Development; Age; Aging; Anti-Inflammatory Agents; Atherosclerosis; Automobile Driving; Biological; Biological Assay; Biological Markers; Blood Cells; Blood Vessels; Blood specimen; Calcium; Cardiac; Cardiology; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Cohort Studies; Communicable Diseases; Coronary; Coronary Arteriosclerosis; Cryopreservation; Development; Diabetes Mellitus; Diagnosis; Early Diagnosis; Elderly; Enrollment; Enzymes; Functional disorder; Genes; Genetic Transcription; Glycolysis; Goals; HIV; HIV Infections; Heart Injuries; Heart failure; Hyperlipidemia; Hypertension; Image; Immune; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin Resistance; Intervention; Ischemic Stroke; Lead; Life Style; Link; Longitudinal Studies; Measures; Mediating; Medicine; Metabolic; Metabolism; Methods; Mitochondria; Morphologic artifacts; Myelogenous; Myeloid Cells; Myocardial Infarction; Opportunistic Infections; Outcome; Oxidative Phosphorylation; Participant; Pathway interactions; Peripheral; Phosphorylation; Plasma; Population; Positioning Attribute; Prevalence; Proteins; RNA; Radiology Specialty; Reporting; Research Design; Research Personnel; Resolution; Risk; Risk Factors; SLC2A1 gene; Smoking; Stress; Substance abuse problem; Surface; T-Lymphocyte; Time; Visit; Work; X-Ray Computed Tomography; aerobic glycolysis; age related; antiretroviral therapy; atherosclerotic plaque rupture; base; burden of illness; calcification; cardiac vasculature; cardiometabolism; cardiovascular disorder risk; cardiovascular health; cardiovascular imaging; cell type; cohort; comorbidity; effective therapy; experience; fatty acid metabolism; follow-up; glucose uptake; immune activation; immune function; innovation; kidney dysfunction; lens; microbial; monocyte; multidisciplinary; nonalcoholic steatohepatitis; novel; novel therapeutics; prevent; programs; success; sudden cardiac death; synergism; systemic inflammatory response; therapeutic target; tool; vascular bed

Older people living with HIV (PLWH) disparately experience an increased risk of cardiovascular disease (CVD) and develop exacerbated age-related cardiometabolic comorbidities compared to uninfected individuals. Multiple risk factors in older people living with HIV including aging, HIV alone, antiretroviral therapy, microbial translocation, traditional CVD risk factors, lifestyle, opportunistic infections, and substance abuse create the "perfect storm" for increased immune activation, systemic inflammation, atherosclerosis, and CVD. Indeed, studies suggest the features driving an elevated risk of CVD include both HIV-specific, and traditional and non- traditional CVD risk factors. Yet, therapeutically targetable biological mechanisms driving an exacerbated HIV- related CVD burden remain unclear. Our previous work identified immunometabolism dysfunction as a mechanism linked to age-related comorbidities in PLWH. Targetable immunometabolic features and immune cell types differentially dysregulated in older PLWH linked to increased CVD risk remain undefined. With a multidisciplinary team including expertise in immunometabolism, cardiology, radiology, and infectious disease, we are uniquely positioned to uncover immunometabolic changes as a key mechanism linking HIV-mediated immune activation and inflammation to CVD comorbidity burden. We will leverage an established cohort of older PLWH at WCM and enroll 100 HIV+ participants (age > 50 years) all on suppressive ART with undetectable plasma HIV RNA in a longitudinal study with three study visits to assess inter- and intraindividual variability in immunometabolic study measures. We will apply a state-of-the-art single cell immunometabolism assay of fresh immune cells obtained from participants in real-time at three time points to overcome artifacts of cryopreservation, profile validated inflammation and cardiac injury biomarkers, and acquire longitudinal advanced cardiovascular and vascular bed CT imaging at baseline and a 36 month follow up time point. Our central hypothesis is that the synergistic effects of HIV and long term ART on CVD comorbidity burden is driven by an exacerbated metabolic reprogramming of monocytes and T cells towards glycolysis in older PLWH on ART. The specific aims are Aim 1: To longitudinally assess the immunometabolic state of monocytes and T cells at single cell resolution, peripheral inflammation, and cardiac injury markers in 100 PLWH > 50 years on stable ART. Aim 2: To quantify the change over time in the degree of subclinical plaque burden across the vasculature in 100 PLWH > 50 years on stable ART and evaluate associations with immunometabolic states of monocyte and T cell subpopulations. The results of this longitudinal study will enhance our understanding of inter- and intraindividual immunometabolism dysfunction in older PLWH linked to subclinical atherosclerosis, provide a roadmap for early detection of CVD based on the individual level and type of risk, and lead to the development of new therapeutics based on exploiting the specific metabolic programs of distinct immune cell populations to mitigate CVD risk in older PLWH.

老年艾滋病毒感染者（PLWH）患心血管疾病的风险不同程度地增加