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： 抗逆转录疗法已将HIV感染转化为 感染（PLWH）衰老。 二十年来，与艾滋病毒相关的CVD的全球负担已逐渐发出。 坚持治疗的艾滋病毒的环境，并在一般情况下强烈预测了CVD事件和死亡率 种群，在造血细胞中获得的突变（不确定潜力的克隆造血症，芯片） 随着年龄的增长而增加，与CVD的风险和过早MI无关 其他传统危险因素。 （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。 突变尚不清楚，最近的研究助长了NLRP3/IL-1β/IL-6途径的作用 重要的是因为这些途径抑制了侵蚀性治疗和基础的靶标 PLWH具有过多的CVD的机制。 芯片中有2折的连衣裙，MCA的流行率很高，但是芯片/MCA和MCA之间的关系 PLWH的CVD风险尚未评估； 在PLWH中，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1525 HIV+和853名HIV退伍军人的前瞻性观察队列 裁定结果，现有的生物标志物上的数据和免疫功能 艾滋病综合临床系统研究网络（CNIC）和1002 PLWH的PLWH 国防部（国防部）同类也将研究艾滋病毒。 Chip mutatip mutatip mutas的开发和CHIP激活炎症以驱动与HIV相关的 动脉粥样硬化。我们提出以下特定目的：目标1： PLWH与未感染的个体更为普遍（AIM 1A）。 突变/MCA与PLWH中CVD和死亡率事件的风险增加有关（AIM 1B）； 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； 带有芯片的PLWH的细胞显示改变基因调节的病理病理病理学的病理激活 特定的免疫细胞类型。 患有艾滋病毒衰老的人的风险有助于确定那些可能从中受益最大的PLWH 免疫调节疗法。 ChIP突变/MCA在PLWH中的CVD发展中起着作用。