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

HIV 感染中新的克隆造血作用不确定性、镶嵌染色体改变和心血管疾病的评估（HIV 中的 ENCODE CVD）

• 批准号: 10753791
• 负责人: Neil C Chi
• 金额: $ 74.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753791
• 关键词: Acquired Immunodeficiency Syndrome; Age; Aging; Atherosclerosis; Biological Assay; Biological Markers; Blood Cells; Cardiovascular Diseases; Cardiovascular system; Cells; Chromosome abnormality; Chronic; Chronic Disease; Clinic Visits; Clinical; Clonal Expansion; Cohort Studies; Communicable Diseases; DNMT3a; Data; Department of Defense; Development; Disease; Epigenetic Process; Ethnic Origin; Evaluation; Event; Face; Gender; General Population; HIV; HIV Infections; Hematopoiesis; Hematopoietic; High Prevalence; Immune; Individual; Infection; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; JAK2 gene; Longitudinal cohort; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Measures; Mutation; Myelogenous; Myeloid Cells; Natural Immunity; Outcome; Pathologic; Pathway interactions; Persons; Placebos; Play; Population; Regulator Genes; Research; Risk; Risk Factors; Role; Smoking; System; Veterans; Viral; Viral Load result; Viral reservoir; Work; adaptive immunity; adjudication; adverse outcome; aged; antiretroviral therapy; biomarker evaluation; cardiovascular disorder risk; cell type; cohort; comorbidity; cost effective; driver mutation; epigenomics; gene regulatory network; genome wide association study; human old age (65+); immune activation; immune function; immunomodulatory therapies; inflammatory marker; mortality; mosaic; multiple omics; novel; novel marker; premature; programs; prospective; systemic inflammatory response

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.

项目摘要/摘要： 抗逆转录病毒疗法已将艾滋病毒感染转化为慢性疾病和艾滋病毒的人群 感染（PLWH）正在衰老。 PLWH发生心血管疾病（CVD）的可能性是 二十年来，与HIV相关的CVD的全球负担增加了两倍。慢性注射和免疫激活 坚持在治疗的艾滋病毒的环境中，并强烈预测CVD事件和死亡率。一般 种群，在造血细胞中获得的突变（不确定潜力的克隆造血，芯片） 随着年龄的增长而增加，与年龄无关的CVD和早产MI的风险增加或 其他传统的风险因素。克隆膨胀的血细胞包含大规模的镶嵌染色体改变 （MCA）也随着年龄的增长而增加，与感染性疾病和死亡率相关，但具有 没有在艾滋病毒中研究。而有芯片的人中的基本机制超出了CVD的风险 突变不清楚，最近的研究表明NLRP3/IL-1β/IL-6途径起作用。这是批判性的 重要的是因为这些途径代表了免疫调节疗法和基础的靶标 PLWH具有超过CVD风险的机制。我们的小组证明了艾滋病毒是相关的 芯片增加了2倍，并且MCA的患病率很高，但芯片/MCA和MCA之间的关系 尚未评估PLWH中的CVD风险；此外，增加芯片/MCA的基本机制 在PLWH中仍然未知。我们计划研究现有的退伍军人老化队列研究生物标志物队列 （VACS BC）是1525 HIV+和853名HIV退伍军人的前瞻性观察队列 调整后的结果，炎症生物标志物的现有数据和免疫功能。另外1000 艾滋病综合临床系统研究网络（CNIC）和1002 PLWH的PLWH 国防部（DOD）队列也将研究。我们假设艾滋病毒是肥沃的底物 芯片突变和MCA的开发以及芯片激活感染以驱动与HIV相关的 动脉粥样硬化。我们提出以下具体目的：目标1：确定芯片突变和MCAS是否为 PLWH与未感染的个体（AIM 1A）更为普遍。并确定是否存在芯片 突变/MCA与PLWH中CVD和死亡率事件的风险增加有关（AIM 1B）；目标2： 通过评估炎症/免疫的标记，阐明HIV中芯片/MCA的机制 激活，表观基因组学和HIV病毒储量大小；目标3：调查免疫的克隆种群是否 带有芯片的PLWH的细胞显示出改变的基因调节程序，以增加病理激活 特异性免疫细胞类型。如果我们的假设正确，则芯片/MCA可以用作CVD的新型生物标志物 艾滋病毒感染衰老的人中的风险，并帮助识别那些可能从中受益最大的PLWH 免疫调节疗法。随着这些特定目标的完成，我们将提高我们对 ChIP突变/MCA在PLWH中的CVD发展中起着作用。