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.

患有艾滋病毒（PLWH）的老年人不同地经历了心血管的风险增加 疾病（CVD）并发展与年龄相关的心脏代谢合并症 未感染的人。艾滋病毒感染的老年人的多个危险因素，包括 衰老，单独艾滋病毒，抗逆转录病毒疗法，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造成了“完美风暴” 免疫激活，全身性炎症，动脉粥样硬化和CVD增加。的确， 研究表明，推动CVD风险升高的特征包括HIV特异性和 传统和非传统CVD风险因素。但是，具有治疗靶向的生物学 驱动加重HIV的CVD负担的机制尚不清楚。我们以前的工作 鉴定出免疫代谢功能障碍是与年龄相关合并症有关的机制 plwh。可靶向的免疫代谢特征和免疫细胞类型在 与CVD风险增加相关的较旧的PLWH仍然不确定。与一个多学科团队 包括免疫代谢，心脏病学，放射学和传染病方面的专业知识，我们是 独特地定位以发现免疫代谢变化作为连接HIV介导的关键机制 免疫激活和对CVD合并症负担的炎症。我们将利用已建立的 WCM的较老PLWH的队列和100名HIV+参与者（年龄> 50岁）都在抑制 在一项纵向研究中，具有未检测到的血浆HIV RNA的艺术，并进行了三次研究访问以评估 免疫代谢研究措施中的个体和内部变异性。我们将应用 最先进的单细胞免疫代谢分析新鲜免疫细胞从 参与者在三个时间点实时实时克服 冷冻保存，剖面验证了炎症和心脏损伤生物标志物，以及 在基线时获取纵向高级心血管和血管床CT成像和36 一个月随访时间点。我们的核心假设是艾滋病毒和长期的协同作用 CVD合并症负担的术语Art是由单核细胞的代谢重编程驱动的 在ART上，在较老的PLWH中朝着糖酵解的T细胞。具体目的是目标1：纵向 评估单核细胞和T细胞的免疫代谢状态在单细胞分辨率，周围 稳定艺术的炎症和100 PLWH> 50年的心脏损伤标记。目标2：量化 随着时间的流逝，脉管系统的亚临床牌匾负担的变化是100 PLWH> 50年的稳定艺术，并评估与免疫代谢状态的关联 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 了解与较老的PLWH中的个体间和内部免疫代谢功能障碍相关的 亚临床动脉粥样硬化，为基于个体的CVD提供了路线图 风险的水平和类型，并导致基于利用的新治疗剂的发展 具有不同免疫细胞群体的特定代谢程序，以减轻较旧的PLWH的CVD风险。