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.

项目摘要/摘要 心血管疾病（CVD）说明了艾滋病毒患者的发病率和死亡率显着 （PWH）抗逆转录病毒疗法（ART）。与艾滋病毒智力个体相比，PWH的体验更高 急性心肌梗塞，心脏猝死和亚临床颈动脉的进展 动脉粥样硬化。慢性感染在PWH中的CVD风险增加中起着至关重要的作用，如 炎症，内皮功能障碍和高凝蛋白的固体和细胞生物标志物升高。一个 引起这种炎症的主要贡献者是肠道层次的CD4+ T细胞的最小恢复和 受干扰的CD4+ T细胞稳态导致免疫失调，肠屏障完整性损害， 和微生物易位。我们表明直肠组织HIV RNA在艺术目的地12周后持续存在 持续无法检测到的血浆病毒载量，这种残留病毒具有复制能力。此外， 直肠HIV RNA与全身注射的生物标志物增加有关，包括TNF-𝛂，D- 二聚体和白介素6。使用包括转录组分析在内的集成的多词方法， 代谢组学，病原体测序以及高密度的细胞因子分析和流式细胞术，我们最近 确定了调节免疫重建和HIV持久性的细胞和分子途径 独立的艺术处理的PWH。使用类似的多摩斯方法和完成 艾滋病毒水库和合并症，基本病毒学/免疫学和心血管的专业知识 临床/翻译研究，我们建议定义直肠HIV持久性如何促进粘膜免疫 失调和细菌易位以驱动感染和亚临床心血管疾病， 提供一个框架来识别新的治疗靶标。提出了三个目标：1）评估关联 直肠组织持久性的标记与全身注射和免疫激活之间； 2）评估 直肠组织持久性的标记与亚临床CVD的患病率/进展之间的关联；和 3）定义HIV直肠持久性促进粘膜免疫失调，细菌的机制 易位和系统性炎症，以增加CVD风险。为此，病毒抑制 从亚特兰大Mac/WIHS组合研究和Emory CFAR招募的ART（n = 100）的PWH（n = 100） 临床部位将进行纵向心血管成像，血管功能评估和配对 血液和直肠组织的取样：1）病毒持久性； 2）全身注射/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 将阐明肠道储层如何促进粘膜免疫失调，细菌易位和 全身性炎症导致CVD合并症，因此预防性和/或治疗性干预 可以识别目标。