Plasma Proteomic and Metabolomic Predictors of Vascular Disease in Treated HIV

项目概要/摘要 HIV 感染者 (PWH) 仍面临较高的 1 型心肌梗死 (T1MI)、缺血性中风和 尽管抗逆转录病毒治疗 (ART) 介导，静脉血栓栓塞 (VTE) 仍高于一般人群 病毒抑制。尽管接受了抗逆转录病毒治疗，许多感染者的全身炎症仍然存在，并预测了这些情况 血管事件，但最佳的介入目标仍不清楚。为了开始解决这些问题，我们 对 CFAR 综合临床网络内近 1,200 名 PWH 进行了初步病例队列研究 维持至少 1 年 ART 介导的病毒抑制并确定的系统 (CNICS) 多种血浆炎症标志物 – 包括微生物易位、CMV 和 色氨酸分解代谢的犬尿氨酸途径 - 预测随后血管事件的风险增加。 我们还观察到，女性（尤其是绝经后年龄）的大多数炎症水平较高。 标记物高于男性，并且趋势表明性别可能会改变炎症与炎症之间的关联 血管事件。该提案将以这些发现为基础，将判定的血管事件增加近一倍 我们研究中的病例（n=135 T1MI，n=74 缺血性中风，n=135 VTE）。我们还将评估血浆 蛋白质组学和代谢组学途径最有力地预测每种事件类型并探索其关联 性别和血浆性激素水平之间以及预测血管疾病的途径。目标1将 使用以下方法评估最能预测 T1MI、缺血性中风和 VTE 的血浆蛋白质组通路 最全面的血浆蛋白质组学平台（SomaScan，针对 7,000 种蛋白质），并验证顶级 通过商业 ELISA 和 VACS BC 队列中的交叉验证得出结果。目标 2 将评估血浆 使用非靶向代谢组学方法对这些血管事件进行代谢组学预测，证实了 进行定量分析，并对先前与血管相关的代谢物进行定量评估 疾病（例如犬尿氨酸和肉毒碱代谢途径）。对于目标 1 和 2，我们将评估是否 与接受治疗的 HIV 患者相比，预测血管疾病结果的最重要的免疫学命中率也有所增加 未感染 HIV 的对照组与 SCOPE 队列中的人口统计数据和健康相关行为相匹配。目标 3 将评估性别和血浆性激素水平与免疫学相关的程度 预测血管疾病的途径以及这些途径是否因绝经状态和绝经状态而异 接受性别肯定荷尔蒙治疗的跨性别女性和顺性别男性。最后，我们将探讨性是否 改变炎症途径和血管疾病之间的关系。这些研究利用了 多学科团队拥有转化免疫学、艾滋病毒发病机制、血管疾病、 代谢组学、流行病学和生物信息学，并将创建可供其他人利用的资源 评估其他疾病结果的预测因子和/或添加额外的分析物。总的来说，这些研究将 加速确定新的干预目标，以减少治疗艾滋病毒感染的多重发病率。

PROJECT SUMMARY/ABSTRACT People with HIV (PWH) remain at higher risk for Type 1 myocardial infarction (T1MI), ischemic stroke, and venous thromboembolism (VTE) than the general population despite antiretroviral therapy (ART)-mediated viral suppression. Systemic inflammation persists in many PWH despite ART and predicts each of these vascular events, but the optimal interventional targets remain unclear. To begin to address these issues, we performed an initial case-cohort study of nearly 1,200 PWH within the CFAR Network of Integrated Clinical Systems (CNICS) who were maintaining at least 1 year of ART-mediated viral suppression and identified several plasma inflammatory markers – including surrogate markers of microbial translocation, CMV, and the kynurenine pathway of tryptophan catabolism - that predicted increased risk of subsequent vascular events. We also observed that women (particularly at post-menopausal ages) had higher levels of most inflammatory markers than men, and trends suggesting that sex may modify the association between inflammation and vascular events. This proposal will build upon these findings by nearly doubling the adjudicated vascular event cases in our study (n=135 T1MI, n=74 ischemic strokes, and n=135 VTE). We will also assess the plasma proteomic and metabolomic pathways most strongly predictive of each event type and explore the associations between sex and plasma sex hormone levels and the pathways that predict vascular disease. Aim 1 will assess the plasma proteomic pathways that most strongly predict T1MI, ischemic stroke, and VTE using the most comprehensive plasma proteomic platform (SomaScan, targeting 7,000 proteins), and validating the top hits with commercial ELISAs and by cross-validation in the VACS BC cohort. Aim 2 will assess the plasma metabolomic predictors of these vascular events using an untargeted metabolomic approach, confirming top hits with quantitative assays, and quantitative assessments of metabolites previously linked to vascular disease (e.g., kynurenine and carnitine metabolic pathways). For both Aims 1 and 2, we will assess whether the top immunologic hits that predict vascular disease outcomes are also increased in treated HIV compared to HIV-uninfected controls matched for demographics and health-related behaviors in the SCOPE cohort. Aim 3 will assess the degree to which sex and plasma sex hormone levels are associated with the immunologic pathways that predict vascular disease and whether these pathways vary by menopausal status and between transgender women on gender-affirming hormonal therapy and cis-men. Lastly, we will explore whether sex modifies the relationship between inflammatory pathways and vascular disease. These studies leverage a multidisciplinary team with expertise in translational immunology, HIV pathogenesis, vascular disease, metabolomics, epidemiology, and bioinformatics and will create a resource that can be leveraged by others to assess predictors of other disease outcomes and/or add additional analytes. Collectively, these studies will accelerate the identification of novel interventional targets to reduce multi-morbidity in treated HIV infection.