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

项目总结/摘要 心血管疾病是艾滋病毒感染者发病率和死亡率的主要原因 (PWH)抗逆转录病毒疗法（ART）。与艾滋病毒血清阴性个体相比， 急性心肌梗死、心源性猝死和亚临床颈动脉粥样硬化进展的风险 动脉粥样硬化慢性炎症在PWH中心血管疾病风险增加中起着至关重要的作用， 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 这种炎症的主要原因是肠道固有层中CD 4 + T细胞的最小恢复， CD 4 + T细胞稳态紊乱，导致免疫失调，损害肠道屏障完整性， 和微生物移位。我们发现，直肠组织HIV RNA在ART治疗12周后仍然存在， 维持不可检测的血浆病毒载量，并且该残留病毒具有复制能力。此外，本发明还 直肠HIV RNA与全身炎症的生物标志物增加相关，包括TNF-α，D- 二聚体和白细胞介素-6。使用包括转录组谱分析的综合多OMICS方法， 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 确定了调节免疫重建和艾滋病毒持久性的细胞和分子途径， ART治疗的PWH的独立队列。使用类似的多OMIC方法和互补 HIV宿主和合并症、基础病毒学/免疫学和心血管疾病方面的专业知识 临床/转化研究，我们建议定义直肠HIV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， 提供了一个框架，以确定新的治疗目标。提出了三个目标：1）评估协会 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 直肠组织持久性标志物与亚临床CVD的患病率/进展之间的相关性;以及 3)定义HIV直肠持久性促进粘膜免疫失调的机制，细菌 易位和全身炎症增加CVD风险。为了实现这一目标， 从亚特兰大MACS/WIHS联合队列研究和Emory CFAR招募的接受ART的PWH（n=100） 临床研究中心将接受纵向心血管成像、血管功能评估， 采集血液和直肠组织样本，以测量：1）病毒持续性; 2）全身炎症/免疫 激活; 3）肠道基因签名;和4）循环微生物组和代谢物组。本研究 将阐明肠道水库如何促进粘膜免疫失调，细菌易位， 导致共病CVD的全身性炎症，因此预防和/或治疗干预 可以识别目标。

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.