Evaluation of Novel Clonal Hematopoiesis Of InDEterminate Potential, Mosaic Chromosomal Alterations and CardioVascular Disease in HIV Infection (ENCODE CVD in HIV)

项目摘要/摘要： 抗逆转录病毒疗法将艾滋病毒感染转变为一种慢性病，艾滋病毒携带者 感染(PLWH)正在老化。PLWH患心血管疾病(CVD)的可能性是过去的两倍 二十年来，全球艾滋病毒相关心血管疾病的负担增加了两倍。慢性炎症与免疫激活 坚持治疗艾滋病毒的环境，对心血管疾病事件和死亡率具有很强的预测性。大体上 群体获得性造血细胞突变(克隆性造血法，CHIP) 随着年龄的增长而增加，并与心血管疾病和早产儿心肌梗死的风险增加有关，与年龄或 其他传统风险因素。克隆扩增的血细胞含有大规模的马赛克染色体改变 (MCAS)也随着年龄的增长而增加，并与传染病和死亡率相关，但 没有在艾滋病毒方面进行过研究。而芯片患者心血管疾病风险过高的潜在机制 突变尚不清楚，最近的研究表明NLRP3/IL-1β/IL-6通路起作用。这是至关重要的 重要的是因为这些通路代表免疫调节治疗的靶点和潜在的 PLWH导致心血管疾病风险过高的机制。我们的小组已经证明了艾滋病毒与 CHIP增加2倍，MCA患病率高，但CHIP/MCA与MCA的关系 PLWH的心血管疾病风险尚未评估；此外，CHIP/MCA增加的潜在机制 在PLWH中的情况仍不清楚。我们计划研究现有的退伍军人老龄化队列研究生物标记物队列 (Vacs BC)，这是一个由1525名HIV+和853名HIV退伍军人组成的前瞻性观察队列，具有广泛的 已判定的结果、炎症生物标志物和免疫功能的现有数据。另外1000人 综合临床系统(CNICs)艾滋病研究中心的PLWH和1002个PLWH 国防部(DoD)的队列也将被研究。我们假设HIV是一种肥沃的底物 芯片突变和MCAS的发展以及该芯片激活炎症驱动HIV相关 动脉硬化。我们提出了以下具体目标：目标1：确定芯片突变和MCAS是否 在PLWH中比未感染的人更普遍(目标1A)。并确定是否存在芯片 突变/MCAS与PLWH中心血管疾病和死亡事件的风险增加有关(目标1B)；目标2： 通过评价炎症/免疫标志物阐明HIV感染CHIP/MCA的机制 激活、表观基因组学和HIV病毒储存库大小；目标3：调查克隆种群是否对 来自PLWH的细胞与芯片显示改变的基因调节程序，增加病理激活 特定的免疫细胞类型。如果我们的假设是正确的，CHIP/MCAS可能成为CVD的一个新的生物标志物 老年HIV感染者的风险，并帮助确定哪些PLWH可能受益最大 免疫调节疗法。随着这些具体目标的完成，我们将推进对 芯片突变/MCAS在PLWH中CVD发生中的作用

Project Summary/Abstract: Antiretroviral therapy has transformed HIV infection into a chronic disease and the population living with HIV infection (PLWH) is aging. PLWH are twice as likely to develop cardiovascular disease (CVD) and in the past two decades, the global burden of HIV-associated CVD has tripled. Chronic inflammation and immune activation persist in the setting of treated HIV and are strongly predictive of CVD events and mortality. In the general population, acquired mutations in hematopoietic cells (clonal hematopoiesis of indeterminate potential, CHIP) increase with age and are associated with an increased risk for CVD and premature MI independent of age or other traditional risk factors. Clonally expanded blood cells contain large scale mosaic chromosomal alterations (mCAs) which also increase with age and are associated with risk for infectious disease, and mortality but have not been studied in HIV. While the underlying mechanisms for excess risk of CVD among people with CHIP mutations is not clear, recent studies suggest the NLRP3/IL-1β/IL-6 pathways play a role. This is critically important because these pathways represent targets for immunomodulatory therapy and underlying mechanisms by which PLWH have an excess risk of CVD. Our group has demonstrated that HIV is associated with a 2-fold increase in CHIP and have a high prevalence of mCA but the relationship between CHIP/mCA and CVD risk in PLWH has not been evaluated; furthermore, the underlying mechanism for increased CHIP/mCA among PLWH remains unknown. We plan to study the existing Veterans Aging Cohort Study Biomarkers Cohort (VACS BC) which is a prospective observational cohort of 1525 HIV+ and 853 HIV- Veterans with extensive adjudicated outcomes, existing data on biomarkers of inflammation, and immune function. An additional 1000 PLWH in the Center for AIDS Research Network of integrated Clinical Systems (CNICS) and 1002 PLWH in the Department of Defense (DoD) cohort will also be studied. We hypothesize that HIV is a fertile substrate for development of CHIP mutations and mCAs and that CHIP activates inflammation to drive HIV-associated atherosclerosis. We propose the following Specific Aims: Aim 1: To determine if CHIP mutations and mCAs are more prevalent in PLWH vs. uninfected individuals (Aim 1A). and to determine whether the presence of CHIP mutations/mCAs are associated with an increased risk of CVD and mortality events in PLWH (Aim 1B); Aim 2: To elucidate the mechanism underlying CHIP/mCA in HIV by evaluation of markers of inflammation/immune activation, epigenomics, and HIV viral reservoir size; Aim 3: To investigate whether clonal populations of immune cells from PLWH with CHIP display altered gene regulatory programs that increase pathologic activation of specific immune cell types. If our hypotheses are correct, CHIP/mCAs may serve as a novel biomarker for CVD risk among people aging with HIV infection and help identify those PLWH who may benefit most from immunomodulatory therapies. With the completion of these specific aims, we will advance our understanding of the role that CHIP mutations/mCAs play in the development of CVD among PLWH.