Investigating Cellular Immunometabolic Mechanisms Underlying HIV-Related Cardiovascular Disease Risk

老年艾滋病毒携带者(PLWH)患心血管疾病的风险增加 疾病(CVD)和与年龄相关的心脏代谢性合并症加重 未受感染的个体。老年艾滋病毒携带者的多种危险因素包括 老龄化、单独感染艾滋病毒、抗逆转录病毒治疗、微生物易位、传统心血管疾病风险 因素、生活方式、机会性感染和药物滥用为 增强免疫活性、全身炎症、动脉粥样硬化和心血管疾病。的确， 研究表明，导致心血管疾病风险增加的特征包括艾滋病毒特异性的，以及 传统和非传统心脑血管疾病的危险因素。然而，具有治疗靶向性的生物 导致艾滋病毒相关心血管疾病负担加剧的机制尚不清楚。我们之前的工作 免疫代谢功能障碍被认为是与年龄相关的合并症有关的机制 PLWH。靶向免疫代谢特征和免疫细胞类型的差异调节 与心血管疾病风险增加有关的较老的PLWH仍未确定。拥有一个多学科团队 包括在免疫代谢、心脏病学、放射学和传染病方面的专业知识，我们 独一无二地发现免疫代谢变化是连接艾滋病毒介导的关键机制 免疫激活和炎症对CVD共病造成负担。我们将利用现有的 WCM的老年PLWH队列，并招募100名HIV+参与者(年龄&>50岁)，全部服用抑制性药物 一项纵向研究中未检测到血浆HIV RNA的ART，共进行了三次研究访问以评估 免疫代谢研究措施中的个体间和个体内变异性。我们将应用一个 新鲜人免疫细胞的单细胞免疫代谢分析 三个时间点的实时参与者，以克服 冷冻保存、轮廓验证的炎症和心脏损伤生物标志物，以及 在基线和36岁时获得纵向先进的心血管和血管床CT成像 月随访时间点。我们的中心假设是HIV和Long的协同效应 心血管疾病共病负担的术语ART是由单核细胞代谢重新编程加剧驱动的 ART上老年PLWH的T细胞向糖酵解方向发展。具体目标是：目标1：纵向 评估单核细胞和T细胞在单个细胞分辨率下的免疫代谢状态 炎症和心脏损伤标记物在100个PLWH&GT；50年的稳定ART。目标2：量化 100例血管系统亚临床斑块负荷程度随时间的变化 PLWH&GT；50年稳定抗逆转录病毒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加强我们的 与老年PLWH相关的个体间和个体内免疫代谢障碍的认识 亚临床动脉粥样硬化，提供基于个体的早期检测心血管疾病的路线图 风险的级别和类型，并导致基于利用 不同免疫细胞群的特定代谢计划，以降低老年PLWH的心血管疾病风险。

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.