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

基本信息

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
项目类别：
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

项目摘要

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.

老年人艾滋病毒感染者（PLWH）患心血管疾病的风险不同程度增加与年龄相关的心脏代谢合并症相比未感染的个体。老年人感染艾滋病毒的多种危险因素包括衰老、单独艾滋病毒、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造成了“完美风暴” 增加免疫激活、全身炎症、动脉粥样硬化和心血管疾病。的确，研究表明，导致 CVD 风险升高的因素包括 HIV 特异性和传统和非传统CVD危险因素。然而，治疗上可靶向的生物导致 HIV 相关 CVD 负担加剧的机制仍不清楚。我们之前的工作确定免疫代谢功能障碍是与年龄相关合并症相关的机制艾滋病病毒感染者。靶向免疫代谢特征和免疫细胞类型差异失调与 CVD 风险增加相关的老年感染者仍不清楚。拥有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，我们具有独特的优势，可以揭示免疫代谢变化作为连接 HIV 介导的关键机制免疫激活和炎症对 CVD 合并症负担的影响。我们将利用既定的 WCM 的老年 PLWH 队列并招募 100 名 HIV+ 参与者（年龄 > 50 岁），全部接受抑制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，并进行了 3 次研究访视以评估免疫代谢研究措施的个体间和个体内变异性。我们将申请一个对新鲜免疫细胞进行最先进的单细胞免疫代谢测定参与者在三个时间点实时克服伪影冷冻保存，分析验证的炎症和心脏损伤生物标志物，以及在基线和 36 处获取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，艾滋病毒和长期感染的协同作用术语 ART 对 CVD 合并症负担的影响是由单核细胞代谢重编程加剧造成的接受 ART 治疗的老年感染者中 T 细胞朝向糖酵解。具体目标是目标 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 100 名接受稳定 ART 治疗超过 50 年的 PLWH 中的炎症和心脏损伤标志物。目标 2：量化整个脉管系统中亚临床斑块负荷程度随时间的变化（100） PLWH > 50 年接受稳定 ART 治疗并评估其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老年感染者个体间和个体内免疫代谢功能障碍与亚临床动脉粥样硬化，为基于个体的 CVD 早期检测提供路线图风险水平和类型，并导致基于开发的新疗法的开发不同免疫细胞群的特定代谢程序可降低老年感染者的心血管疾病风险。