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

项目摘要/摘要 心血管疾病(CVD)在艾滋病毒携带者中占很大的发病率和死亡率 (PWH)关于抗逆转录病毒治疗(ART)。与HIV血清阴性的人相比，PWH的经历更高 急性心肌梗死、心脏性猝死和亚临床颈动脉病变进展的风险 动脉硬化。慢性炎症在PWH患者心血管风险增加中起关键作用，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 这种炎症的主要原因是肠道固有层和肠道固有层中CD4+T细胞的最小恢复 CD4+T细胞动态平衡失调，导致免疫失调，肠道屏障完整性受损， 和微生物易位。我们发现直肠组织中的hiv rna在接受抗逆转录病毒治疗12周后仍然存在。 持续的无法检测到的血浆病毒载量，并且这种残留病毒具有复制能力。另外， 直肠HIVRNA与全身炎症的生物标志物增加有关，包括肿瘤坏死因子-𝛂、D- 二聚体和白介素6。使用集成的多OMICS方法，包括转录组分析， 代谢组学、病原体测序、高密度细胞因子图谱和流式细胞术，我们最近 在两个阶段确定了调节免疫重建和HIV持久性的细胞和分子途径 接受抗逆转录病毒治疗的威斯康星医院的独立队列。使用类似的多组学方法和互补 在艾滋病毒宿主和合并症、基础病毒学/免疫学和心血管疾病方面的专业知识 临床/翻译研究，我们建议定义直肠HIV持续存在如何促进粘膜免疫 调节失调和细菌移位导致炎症和亚临床心血管疾病， 为确定新的治疗靶点提供框架。提出了三个目标：1)评估社团 直肠组织持久性标志物与全身炎症和免疫激活的关系；2)评估 直肠组织持久性标志物与亚临床心血管疾病流行/进展的关系 3)确定HIV直肠滞留促进粘膜免疫失调的机制，细菌 易位和全身性炎症增加心血管疾病的风险。为了做到这一点，病毒被压制了 PWH on ART(n=100)，从亚特兰大MACS/WIHS联合队列研究和Emory CFAR招募 临床站点将接受纵向心血管成像、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。本研究 将阐明肠道储备物如何促进粘膜免疫失调、细菌易位和 导致并发心血管疾病的全身性炎症，因此预防性和/或治疗性干预 目标是可以识别的。

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.