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）：在成功抑制艾滋病毒复制后，心血管疾病（CVD）是艾滋病毒感染（HIV+）患者面临的越来越重要的健康问题。抗逆转录病毒疗法本身，常规的弗雷明汉危险因素，贫血，肝炎共同感染和肾脏疾病都是HIV+患者的危险因素，但是与未感染（HIV-）相比，这些因素并不能完全解释HIV+中CVD的过量风险。基于鼠模型的很大程度上获得的见解，进行性动脉粥样硬化很大程度上会引起CVD，这反过来又是由于不适当的脂质代谢以及先天和适应性免疫系统的激活而引起的。虽然免疫细胞功能的改变是HIV和CVD发病机理的共同特征，但尚不清楚与HIV患者相比，HIV+患者中CVD+人中CVD+人中CVD的过量风险是否与人类的过量风险有关。为了回答这些问题，我们将利用退伍军人老化队列研究（VACS）生物标志物队列，这是1525 HIV+和853名HIV退伍军人的纵向，前瞻性观察队列。该队列的重要优势包括现有的存储冷冻保存细胞，炎症生物标志物，凝结和单核细胞激活的数据；纵向调查，医疗保险，医疗补助，死亡率和国家死亡指数数据；全面访问包括药房记录在内的整个VA电子病历；并裁定VA内外发生的CVD事件。我们建议从2005 - 2006年收集的现有冷冻保存细胞和（2）裁定CVD事件（即急性心肌梗死，冠状动脉心脏病，缺血性中风，心力衰竭和CVD死亡），以测量从2005 - 2006年收集的现有冷冻保存细胞的免疫细胞类型和亚群。我们的具体目的是：（1）确定HIV+和HIV人群中pro和抗动物性免疫细胞的数量和比例以及天真的记忆/效应T细胞； （2）确定这些免疫细胞类型和亚群是否与普遍和入射CVD独立相关； （3）确定它们是否介导HIV感染与入射CVD之间的关联。 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与艾滋病毒相比，子集将解释艾滋病毒+人中CVD的过多风险。如果我们的假设是正确的，我们将提高对免疫功能如何有助于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将新的风险因素纳入当前的CVD风险预测工具。此外，VACS生物标志物队列将成为对免疫功能和CVD以及其他肺和血液疾病感兴趣的更大的研究社区的宝贵资源。