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: 10491277
• 负责人: Michael Jay Corley
• 金额: $ 59.94万
• 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/10491277
• 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; Persons; 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; syndemic; 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）的心血管疾病风险增加 疾病（CVD），并发生年龄相关的心脏代谢合并症加重， 未受感染的人。老年艾滋病毒感染者的多种风险因素，包括 老龄化，单纯HIV，抗逆转录病毒治疗，微生物易位，传统CVD风险 因素、生活方式、机会性感染和药物滥用创造了“完美风暴”， 增加的免疫激活、全身性炎症、动脉粥样硬化和CVD。的确， 研究表明，导致CVD风险升高的特征包括HIV特异性， 传统和非传统CVD危险因素。然而，治疗靶向生物 导致HIV相关CVD负担加重的机制尚不清楚。我们以前的工作 将免疫代谢功能障碍确定为与年龄相关合并症相关的机制， PLWH。免疫系统中靶向免疫代谢特征和免疫细胞类型差异失调 与心血管疾病风险增加相关的老年PLWH仍不明确。多学科团队 包括免疫代谢、心脏病学、放射学和传染病方面的专业知识， 独特的定位，以揭示免疫代谢变化作为连接艾滋病毒介导的 免疫激活和炎症对CVD合并症负担的影响。我们将利用现有的 在WCM的老年PLWH队列中，招募100名HIV+参与者（年龄> 50岁），全部接受抑制性治疗， 在一项纵向研究中，使用无法检测到的血浆HIV RNA进行ART，其中有三次研究访视，以评估 免疫代谢研究指标的个体间和个体内变异性。我们将采用 获得的新鲜免疫细胞的最新单细胞免疫代谢测定 参与者在三个时间点进行实时测试， 冷冻保存，概况验证的炎症和心脏损伤生物标志物，和 在基线时获得纵向高级心血管和血管床CT成像， 月随访时间点。我们的中心假设是，艾滋病毒和长期的协同效应， 长期ART对CVD合并症负荷的影响是由单核细胞代谢重编程加剧引起的 和T细胞向糖酵解在老年PLWH对ART的具体目标是目的1：纵向 以单细胞分辨率评估单核细胞和T细胞的免疫代谢状态，外周血 目的2：量化100例> 50岁的PLWH患者在稳定ART治疗中的炎症和心脏损伤标志物。 在100例中，跨脉管系统的亚临床斑块负荷程度随时间的变化 PLWH > 50岁，接受稳定的ART治疗，并评估与免疫代谢状态的相关性， 单核细胞和T细胞亚群。这项纵向研究的结果将增强我们的 了解与老年PLWH相关的个体间和个体内免疫代谢功能障碍 亚临床动脉粥样硬化，提供了一个基于个体的CVD早期检测路线图 风险的水平和类型，并导致开发基于利用 不同免疫细胞群体的特定代谢程序，以减轻老年PLWH的CVD风险。