Elucidating the role of the gut reservoir and inflammation in driving cardiovascular disease among persons living with HIV

阐明肠道储存库和炎症在艾滋病毒感染者心血管疾病中的作用

• 批准号: 10670393
• 负责人: Christina Gavegnano
• 金额: $ 74.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670393
• 关键词: Acquired Immunodeficiency Syndrome; Acute myocardial infarction; Automobile Driving; Bacterial Translocation; Biological Markers; Biometry; Blood Vessels; Blood specimen; C-reactive protein; CD14 gene; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Diseases; Carotid Atherosclerotic Disease; Cells; Chronic; Clinical; Cohort Studies; Communicable Diseases; DNA; Data; Development; Disease; Fibrin fragment D; Flow Cytometry; Functional disorder; Gastrointestinal tract structure; Goals; Gut Mucosa; HIV; HIV Infections; High Risk Woman; Homeostasis; Immune; Immunology; Impairment; Individual; Inflammation; Inflammatory; Interleukin-6; Lamina Propria; Life Expectancy; Link; Lymphocyte; Magnetic Resonance Imaging; Measures; Mediating; Modernization; Molecular; Morbidity - disease rate; Mucous Membrane; Organ; Pathway interactions; Persons; Plasma; Play; Population; Prevalence; RNA; Rectum; Residual state; Risk; Risk Factors; Role; Severities; Site; Suspensions; TNF gene; Testing; Therapeutic Intervention; Time; Tissues; Translational Research; United States; Vascular Diseases; Vasodilation; Viral; Viral Load result; Virus; aged; antiretroviral therapy; arterial stiffness; arterial tonometry; brachial artery; cardiovascular disorder risk; cardiovascular imaging; clinical research site; cohort; comorbidity; cytokine; density; drug development; early onset; endothelial dysfunction; experience; genetic signature; high risk; high risk men; immune activation; immune reconstitution; improved; metabolome; metabolomics; microbial; microbiome; mortality; multidisciplinary; multiple omics; new therapeutic target; novel therapeutics; pathogen; prevent; preventive intervention; programs; progression risk; recruit; rectal; restoration; sudden cardiac death; systemic inflammatory response; virology

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) accounts for significant morbidity and mortality among persons living with HIV (PWH) on antiretroviral therapy (ART). Compared to HIV-seronegative individuals, PWH experience higher risk of acute myocardial infarction, sudden cardiac death, and progression of subclinical carotid atherosclerosis. Chronic inflammation plays a crucial role in increased CVD risk among PWH, as indicated by elevated soluble and cellular biomarkers of inflammation, endothelial dysfunction, and hypercoagulation. A major contributor to this inflammation is the minimal restoration of CD4+ T cells in gut lamina propria and disturbed CD4+ T cell homeostasis which results in immune dysregulation, compromised gut barrier integrity, and microbial translocation. We showed that rectal tissue HIV RNA persists after 12 weeks of ART despite sustained undetectable plasma viral loads and that this residual virus was replication-competent. Additionally, rectal HIV RNA was associated with increased biomarkers of systemic inflammation, including TNF-𝛂, D- Dimer, and interleukin-6. Using an integrated multi-OMICS approach including transcriptomal profiling, metabolomics, pathogen sequencing, and high-density cytokine profiling and flow cytometry, we recently identified cellular and molecular pathways that regulate immune reconstitution and HIV persistence in two independent cohorts of ART-treated PWH. Using a similar multi-OMICs approach and complementary expertise in HIV reservoirs and comorbidities, basic virology/immunology, and cardiovascular clinical/translational research, we propose to define how rectal HIV persistence promotes mucosal immune dysregulation and bacterial translocation to drive inflammation and subclinical cardiovascular disease, providing a framework to identify new therapeutic targets. Three aims are proposed: 1) Assess association between markers of rectal tissue persistence and systemic inflammation and immune activation; 2) Assess association between markers of rectal tissue persistence and prevalence/progression of subclinical CVD; and 3) Define mechanisms by which HIV rectal persistence promotes mucosal immune dysregulation, bacterial translocation, and systemic inflammation to increase CVD risk. To accomplish this, virally-suppressed PWH on ART (n=100) recruited from the Atlanta MACS/WIHS Combined Cohort Study and Emory CFAR clinical sites will undergo longitudinal cardiovascular imaging, vascular function assessments, and paired sampling of blood and rectal tissue to measure: 1) viral persistence; 2) systemic inflammation/immune activation; 3) gut gene signatures; and 4) circulating microbiome and metabolome. This study will elucidate how the gut reservoir promotes mucosal immune dysregulation, bacterial translocation, and systemic inflammation leading to comorbid CVD so that preventative and/or therapeutic intervention targets can be identified.

项目概要/摘要 心血管疾病 (CVD) 是艾滋病毒感染者显着的发病率和死亡率的原因 （PWH）抗逆转录病毒治疗（ART）。与 HIV 血清阴性个体相比，PWH 的经历更高 急性心肌梗塞、心源性猝死和亚临床颈动脉进展的风险 动脉粥样硬化。慢性炎症在增加感染者 CVD 风险中起着至关重要的作用，如下所示： 炎症、内皮功能障碍和高凝状态的可溶性和细胞生物标志物升高。一个 造成这种炎症的主要原因是肠道固有层中 CD4+ T 细胞的恢复极少， CD4+ T 细胞稳态紊乱，导致免疫失调、肠道屏障完整性受损， 和微生物易位。我们发现，尽管 ART 治疗 12 周后，直肠组织 HIV RNA 仍然存在 持续检测不到的血浆病毒载量，并且这种残留病毒具有复制能力。此外， 直肠 HIV RNA 与全身炎症生物标志物增加相关，包括 TNF-α、D- 二聚体和白细胞介素6。使用集成的多组学方法，包括转录组分析， 代谢组学、病原体测序、高密度细胞因子分析和流式细胞术，我们最近 确定了在两个细胞中调节免疫重建和艾滋病毒持续性的细胞和分子途径 接受 ART 治疗的 PWH 的独立队列。使用类似的多组学方法和互补 HIV 储存库和合并症、基础病毒学/免疫学和心血管方面的专业知识 临床/转化研究，我们建议定义直肠艾滋病毒持续性如何促进粘膜免疫 失调和细菌易位导致炎症和亚临床心血管疾病， 提供一个框架来确定新的治疗靶点。提出了三个目标：1）评估关联 直肠组织持久性标记物与全身炎症和免疫激活之间的关系； 2）评估 直肠组织持续性标记物与亚临床 CVD 患病率/进展之间的关联；和 3) 明确 HIV 直肠持续存在促进粘膜免疫失调、细菌感染的机制 易位和全身炎症会增加 CVD 风险。为了实现这一目标，需要抑制病毒 接受 ART 治疗的 PWH (n=100) 招募自亚特兰大 MACS/WIHS 联合队列研究和埃默里 CFAR 临床中心将进行纵向心血管成像、血管功能评估和配对 采集血液和直肠组织样本以测量：1) 病毒持久性； 2）全身炎症/免疫 激活; 3）肠道基因特征； 4) 循环微生物组和代谢组。这项研究 将阐明肠道储存库如何促进粘膜免疫失调、细菌易位和 全身炎症导致合并 CVD，因此需要预防和/或治疗干预 可以确定目标。