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： 抗逆转录病毒治疗已将艾滋病毒感染转变为慢性疾病，艾滋病毒感染者 感染者（PLWH）正在老龄化 PLWH 患心血管疾病（CVD）的可能性是过去的两倍。 二十年来，与艾滋病毒相关的心血管疾病的全球负担增加了两倍。 在接受治疗的 HIV 环境中持续存在，并且总体上强烈预测 CVD 事件和死亡率。 人群，造血细胞获得性突变（不确定潜力的克隆造血，CHIP） 随着年龄的增长而增加，并且与 CVD 和早发 MI 的风险增加相关，与年龄或年龄无关 其他传统的危险因素。克隆扩增的血细胞含有大规模的镶嵌染色体改变。 （mCA）也随着年龄的增长而增加，并与传染病和死亡率的风险相关，但 尚未对 HIV 患者进行研究，而 CHIP 患者罹患 CVD 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 通路发挥着至关重要的作用。 重要的是，因为这些途径代表了免疫调节治疗的目标和潜在的 PLWH 罹患 CVD 风险过高的机制已证明与 HIV 相关。 CHIP 增加 2 倍，并且 mCA 患病率很高，但 CHIP/mCA 与 此外，尚未评估 PLWH 的 CVD 风险；此外，CHIP/mCA 增加的根本机制 我们计划研究现有的退伍军人衰老队列研究生物标志物队列。 (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， 裁决结果、炎症生物标志物和免疫功能的现有数据。 艾滋病研究中心网络综合临床系统 (CNICS) 的 PLWH 和 1002 名 PLWH 我们还将对国防部 (DoD) 队列进行研究，认为艾滋病毒是一种可繁殖的基质。 CHIP 突变和 mCA 的发展以及 CHIP 激活炎症以驱动 HIV 相关的 我们提出以下具体目标： 目标 1：确定 CHIP 突变和 mCA 是否与动脉粥样硬化有关。 与未感染者相比，在 PLWH 中更为普遍（目标 1A），并确定是否存在 CHIP。 突变/mCA 与 PLWH 的 CVD 和死亡事件风险增加相关（目标 1B）； 通过评估炎症/免疫标志物来阐明 HIV 中 CHIP/mCA 的潜在机制 激活、表观基因组学和 HIV 病毒库大小；目标 3：研究免疫克隆群体是否 来自携带 CHIP 的 PLWH 细胞显示出基因调控程序，可增加 如果我们的假设正确，CHIP/mCA 可以作为 CVD 的新型生物标志物。 感染艾滋病毒的老年人面临的风险，并帮助确定那些可能从中受益最多的艾滋病病毒感染者 随着这些具体目标的完成，我们将加深对免疫调节疗法的理解。 CHIP 突变/mCA 在 PLWH 中 CVD 发展中发挥的作用。