Plasma Proteomic and Metabolomic Predictors of Vascular Disease in Treated HIV

项目摘要/摘要 艾滋病毒携带者(PWH)仍然是1型心肌梗死(T1MI)、缺血性中风和 尽管抗逆转录病毒疗法(ART)介导，静脉血栓栓塞症(VTE)仍高于普通人群 病毒抑制。尽管抗逆转录病毒治疗，许多PWH患者仍存在全身性炎症，并可预测其中的每一种。 血管事件，但最佳的介入靶点仍不清楚。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例PWH进行了初步病例队列研究 系统(CNIC)保持至少一年的ART介导的病毒抑制，并确认 几种血浆炎症标志物--包括微生物易位的替代标志物、巨细胞病毒和 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)的大多数炎症性细胞因子水平较高。 标记物多于男性，而且有趋势表明性行为可能会改变炎症和 血管事件。这项提案将在这些发现的基础上，将判定的血管事件增加近一倍 本组病例(T1MI 135例，缺血性卒中74例，VTE 135例)。我们还将评估血浆 蛋白质组和代谢组途径对每种事件类型的预测作用最强，并探索它们之间的关联 性和血浆性激素水平与预测血管疾病的途径之间的关系。目标1将 评估最能预测T1 MI、缺血性卒中和VTE的血浆蛋白质组途径 最全面的血浆蛋白质组平台(SomaScan，目标为7,000个蛋白质)，并验证顶级 通过商业ELISA和Vacs BC队列的交叉验证来命中。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的代谢学预测因子，证实TOP 对先前与血管有关的代谢物进行定量分析和定量评估 疾病(例如，犬尿氨酸和肉碱代谢途径)。对于目标1和目标2，我们将评估是否 预测血管疾病预后的最高免疫学命中率在接受治疗的艾滋病毒患者中也有所增加 在范围队列中，未感染艾滋病毒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 接受性别肯定荷尔蒙治疗的变性人女性和顺式男性。最后，我们将探索性行为是否 改变炎症途径和血管疾病之间的关系。这些研究利用了 拥有翻译免疫学、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，并将创建一个可供其他人利用的资源 评估其他疾病结局的预测因素和/或增加额外的分析物。总的来说，这些研究将 加快确定新的干预靶点，以减少治疗艾滋病毒感染中的多种发病率。

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.