Immune function and the risk of cvd among HIV infected and uninfected veterans

描述(申请人提供)：随着成功抑制艾滋病毒复制后长期存活率的提高，心血管疾病(CVD)成为艾滋病毒感染者(HIV+)面临的日益重要的健康问题。抗逆转录病毒治疗本身、传统的弗雷明翰危险因素、贫血、丙型肝炎合并感染和肾脏疾病都是艾滋病毒感染者中的危险因素，但这些因素并不能完全解释艾滋病毒感染者与未感染者(HIV-)相比心血管疾病风险过高的原因。根据大量从小鼠模型中获得的见解，进行性动脉粥样硬化主要导致心血管疾病，而心血管疾病又是由不适当的脂代谢和天然免疫系统和获得性免疫系统的激活引起的。虽然免疫细胞功能的改变是HIV和CVD发病机制的共同特征，但尚不清楚外周血单核细胞和T细胞亚群的激活、数量和比例是否与人类CVD的发生有关，并解释了HIV+人群与HIV-人群相比CVD的额外风险。为了回答这些问题，我们将利用退伍军人老龄化队列研究(VAS)生物标记物队列，这是一个纵向的前瞻性观察队列，包括1525名艾滋病毒+和853名艾滋病毒阳性的退伍军人。这一队列的重要优势包括现有的冷冻保存细胞，炎症、凝血和单核细胞激活的生物标志物数据；纵向调查、Medicare、Medicaid、死亡率和国家死亡指数数据；全面访问包括药房记录在内的整个退伍军人管理局电子医疗记录；以及退伍军人事务部内外发生的已裁决的心血管事件。我们建议测量2005-2006年收集的现有冷冻保存细胞的免疫细胞类型和亚群，以及(2)判断2005-2017年的CVD事件(即急性心肌梗死、冠心病、缺血性中风、心力衰竭和CVD死亡)。我们的具体目标是：(1)确定HIV+和HIV-人群中支持和抗动脉粥样硬化的免疫细胞以及幼稚T细胞和记忆/效应T细胞的数量和比例；(2)确定这些免疫细胞类型和亚群是否与流行和发生CVD独立相关；(3)确定它们是否在HIV感染和发生CVD之间起中介作用。我们假设，(1)具有较高比例的前动脉粥样硬化(例如，中间单核细胞和TH1细胞)和较低比例的抗动脉粥样硬化(例如，TH调节细胞)的免疫细胞和/或(3)免疫衰老的证据增加(例如，幼稚的T细胞：记忆T细胞的比例较低)将增加发生心血管疾病的风险，并且这些类型的免疫细胞亚群将解释与艾滋病毒携带者相比，HIV+人群中心血管疾病的额外风险。如果我们的假设是真的，我们将推进我们对免疫功能如何促进HIV+和HIV携带者心血管疾病的理解，同时也可能为未来的心血管疾病干预研究确定新的靶点，并将新的风险因素纳入当前的心血管疾病风险预测工具。此外，Vacs生物标记物队列将成为对免疫功能、心血管疾病和其他肺和血液疾病感兴趣的更大研究社区的宝贵资源。

DESCRIPTION (provided by applicant): With improving long-term survival after successful suppression of HIV replication, cardiovascular disease (CVD) is an increasingly important health problem facing HIV infected (HIV+) people. Antiretroviral therapy itself, conventional Framingham risk factors, anemia, hepatitis C co-infection, and renal disease are all risk factors among HIV+ people, but these factors do not completely explain the excess risk of CVD among HIV+ compared to uninfected (HIV-) people. Based on insights gained largely from murine models, progressive atherosclerosis largely causes CVD which is in turn caused by inappropriate lipid metabolism and activation of the innate and adaptive immune systems. While alteration in immune cell function is a shared feature of HIV and CVD pathogenesis, it is not known whether the activation, number and or proportion of peripheral circulating monocyte and T cell subsets are associated with incident CVD in humans and explain the excess risk of CVD among HIV+ people compared to HIV- people. To answer these questions, we will leverage the Veterans Aging Cohort Study (VACS) biomarker cohort, a longitudinal, prospective observational cohort of 1525 HIV+ and 853 HIV- Veterans. Important strengths of this cohort include existing stored cryopreserved cells, data on biomarkers of inflammation, coagulation, and monocyte activation; longitudinal survey, Medicare, Medicaid, mortality and national death index data; comprehensive access to the entire VA electronic medical record including pharmacy records; and adjudicated CVD events occurring within and outside the VA. We propose to measure immune cell types and subsets from existing cryopreserved cells collected in 2005-2006 and (2) to adjudicate CVD events (i.e., acute myocardial infarction, coronary heart disease, ischemic stroke, heart failure, and CVD death) from 2005-2017. Our specific aims are to: (1) Determine the number and proportion of pro and anti-atherosclerotic immune cells as well as naive and memory/effector T cells among HIV+ and HIV- people; (2) Determine if these immune cell types and subsets are independently associated with prevalent and incident CVD; (3) Determine whether they mediate the association between HIV infection and incident CVD. We hypothesize that people with (1) a higher proportion of proatherosclerotic (e.g., intermediate monocytes and TH1 cells) and a lower proportion of anti-atherosclerotic (e.g., TH regulatory cells) immune cells, respectively, and/or (3) increased evidence of immunosenescence (e.g., a low ratio of naive: memory T cells) will have an increased risk of incident CVD and that these types of immune cell subsets will explain the excess risk of CVD among HIV+ people compared to HIV- people. If our hypotheses are true, we will advance our understanding of how immune function contributes to CVD for HIV+ and HIV- people while also potentially identifying new targets for future CVD intervention studies and new risk factors for inclusion into current CVD risk prediction tools. In addition, the VACS biomarker cohort will become a valuable resource for the larger research community interested in immune function and CVD and other lung and blood disorders.