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

HIV感染者和未感染者的免疫功能和CVD风险

• 批准号: 9268918
• 负责人: MATTHEW S FREIBERG
• 金额: $ 28.92万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-27 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268918
• 关键词: Immune; function; risk; cvd; among

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.

描述（由申请人提供）：随着成功抑制 HIV 复制后长期生存率的提高，心血管疾病 (CVD) 已成为 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、传统弗雷明汉危险因素、贫血、丙型肝炎合并感染和肾脏疾病都是 HIV+ 人群的危险因素，但这些因素并不能完全解释 HIV+ 与未感染者 (HIV-) 相比，CVD 风险过高。根据主要从小鼠模型获得的见解，进行性动脉粥样硬化在很大程度上导致心血管疾病，而心血管疾病又是由不适当的脂质代谢以及先天性和适应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，但尚不清楚外周循环单核细胞和 T 细胞亚群的激活、数量和或比例是否与人类 CVD 事件相关，并解释了 HIV 阳性人群与 HIV 阴性人群相比，CVD 风险过高的原因。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，这是一个由 1525 名 HIV+ 和 853 名 HIV- 退伍军人组成的纵向前瞻性观察队列。该队列的重要优势包括现有的冷冻保存细胞、炎症、凝血和单核细胞激活生物标志物的数据；纵向调查、医疗保险、医疗补助、死亡率和国家死亡指数数据；全面访问整个 VA 电子病历，包括药房记录；以及 VA 内外发生的 CVD 事件的裁决。我们建议测量 2005-2006 年收集的现有冷冻细胞的免疫细胞类型和亚群，以及 (2) 判定 2005-2017 年的 CVD 事件（即急性心肌梗塞、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- 人群中促动脉粥样硬化免疫细胞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流行和偶发的 CVD 独立相关； (3) 确定它们是否介导 HIV 感染与 CVD 事件之间的关联。我们假设，(1) 促动脉粥样硬化免疫细胞比例较高（例如中间单核细胞和 TH1 细胞）和抗动脉粥样硬化免疫细胞比例较低（例如 TH 调节细胞）和/或 (3) 免疫衰老证据增加（例如初始：记忆 T 细胞比例较低）的人发生 CVD 的风险会增加，并且这些类型的免疫细胞 子集将解释 HIV 阳性人群与 HIV 阴性人群相比 CVD 风险过高的原因。如果我们的假设成立，我们将加深对免疫功能如何促进 HIV+ 和 HIV- 人群 CVD 的理解，同时也有可能确定未来 CVD 干预研究的新目标以及纳入当前 CVD 风险预测工具的新风险因素。此外，VACS 生物标志物队列将成为对免疫功能、CVD 以及其他肺部和血液疾病感兴趣的更大研究界的宝贵资源。