Plasma Proteomic and Metabolomic Predictors of Vascular Disease in Treated HIV

项目概要/摘要 HIV感染者（PWH）仍有较高的1型心肌梗死（T1 MI）、缺血性卒中和 静脉血栓栓塞症（VTE）比一般人群，尽管抗逆转录病毒治疗（ART）介导 病毒抑制全身炎症持续存在于许多PWH尽管ART和预测每一个这些 血管事件，但最佳介入靶点仍不清楚。为了开始解决这些问题，我们 在CFAR综合临床网络内对近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 几种血浆炎症标志物-包括微生物易位的替代标志物，CMV，以及 色氨酸催化剂的犬尿氨酸途径-预测随后血管事件的风险增加。 我们还观察到，女性（特别是绝经后年龄的女性）的大多数炎症性细胞因子水平较高， 与男性相比，性别可能会改变炎症与 血管事件该提案将在这些发现的基础上，将裁定的血管事件增加近一倍 在我们的研究中，有135例T1 MI，74例缺血性卒中和135例VTE。我们还将评估血浆 蛋白质组学和代谢组学途径对每种事件类型的预测性最强，并探讨其相关性。 性和血浆性激素水平之间的联系以及预测血管疾病的途径。目标1将 评估血浆蛋白质组学途径，最强有力地预测T1 MI，缺血性卒中，和静脉血栓栓塞使用 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 通过商业ELISA和VACS BC组群中的交叉验证的命中。目标2将评估血浆 使用非靶向代谢组学方法，这些血管事件的代谢组学预测因子，证实了 定量分析命中，以及先前与血管相关的代谢物的定量评估 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 与对照组相比，治疗组中预测血管疾病结局的最高免疫学命中率也有所增加， 在SCOPE队列中，未感染HIV的对照组与人口统计学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功能相关的程度。 预测血管疾病的途径，以及这些途径是否因绝经状态而异， 接受性别确认荷尔蒙疗法的变性妇女和顺性男子。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，在转化免疫学、HIV发病机制、血管疾病 代谢组学，流行病学和生物信息学，并将创建一个资源，可以利用他人， 评估其他疾病结果的预测因子和/或添加额外的分析物。这些研究将 加速确定新的干预靶点，以减少已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.