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HIV复制后长期生存率的提高，心血管疾病（CVD）是HIV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Framingham危险因素、贫血、丙型肝炎合并感染和肾脏疾病都是HIV+人群中的危险因素，但这些因素并不能完全解释与未感染（HIV-）人群相比，HIV+人群中心血管疾病的风险过高。基于从小鼠模型中获得的见解，进行性动脉粥样硬化在很大程度上导致心血管疾病，而心血管疾病又由不适当的脂质代谢和先天和适应性免疫系统的激活引起。虽然免疫细胞功能的改变是HIV和CVD发病机制的共同特征，但目前尚不清楚外周循环单核细胞和T细胞亚群的激活、数量和比例是否与人类CVD的发生有关，也不清楚为什么HIV+人群比HIV-人群患CVD的风险更高。为了回答这些问题，我们将利用退伍军人衰老队列研究（VACS）生物标志物队列，这是一项纵向、前瞻性观察队列，包括1525名HIV+和853名HIV-退伍军人。该队列的重要优势包括现有的冷冻保存细胞，炎症、凝血和单核细胞活化的生物标志物数据；纵向调查、医疗保险、医疗补助、死亡率和全国死亡指数数据；全面访问整个VA电子医疗记录，包括药房记录；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，并(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-人群中促和抗动脉粥样硬化免疫细胞以及幼稚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CVD的流行和发生率独立相关；(3)确定它们是否介导了HIV感染与CVD发生之间的关联。我们假设(1)更高比例的患者proatherosclerotic(例如,中间单核细胞和TH1细胞)和较低比例的anti-atherosclerotic(例如,TH监管细胞)的免疫细胞,分别和/或(3)增加免疫衰老的证据(例如,天真的比率非常低:记忆T细胞)将事件心血管疾病的风险增加,这些类型的免疫细胞子集将解释多余的心血管疾病的风险比艾滋病毒HIV阳性的人,人。如果我们的假设是正确的，我们将进一步了解免疫功能如何促进HIV+和HIV-人群的CVD，同时也可能为未来的CVD干预研究确定新的靶点，并为当前的CVD风险预测工具确定新的风险因素。此外，VACS生物标志物队列将成为对免疫功能、心血管疾病和其他肺部和血液疾病感兴趣的大型研究界的宝贵资源。

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.