Integrated analysis of CVD risk in HIV: gut microbiota, immune function and metabolites

总结/摘要 我们之前在HIV队列研究中的工作提供了对病毒，炎症，免疫激活和 抗逆转录病毒治疗相关的HIV相关CVD风险因素。然而，对它的病理生理学的理解 仍然不完整。新出现的证据表明，肠道微生物群（GMB）在艾滋病毒感染期间发生了变化 与免疫激活增加和代谢产物谱破坏相关，但GMB在HIV-1中的作用 相关的CVD未知。我们的初步数据显示，在HIV感染中，动脉粥样硬化的进展是 与较高的循环sCD 14（单核细胞活化的标志物）和色氨酸增加相关 猫这项初步工作提出了两个有前途的候选人联系GMB和心血管疾病的风险在艾滋病毒 感染，我们建议使用集成的“组学”方法进行研究。除了这些假设- 驱动的研究目标，我们还将产生新的假设连接GMB，宿主免疫激活， 与CVD风险相关的代谢组学特征。我们将利用妇女机构间艾滋病毒研究（WIHS） 和多中心艾滋病队列研究（MACS）>20年的生物标本，动脉粥样硬化和其他随访 心血管疾病指标和艾滋病毒参数。我们每半年进行一次的纵向测量， 根据长期HIV治疗、疾病进展标志物（CD 4 + T细胞计数、病毒载量），以及 科摩罗，包括匹配的HIV未感染者。在这个项目中，我们将扩大我们的 与领先的实验室建立合作，收集400名女性和男性（约65%）的多维数据 其中HIV阳性），包括粪便GMB宏基因组学、血清和细胞炎症以及免疫学 标志物（sCD 14、单核细胞转录组学）、代谢组学和测量（颈动脉超声成像 随访4年以上）。这个深入研究小组的研究结果将扩展到更大的样本， 746名男性和女性的代谢组学和纵向动脉粥样硬化数据。在这个项目中，我们将有 有机会确定免疫激活和代谢物的作用，GMB在CVD，这可能是 特异于HIV+个体，或在HIV背景下加重。

Summary/Abstract Our prior work in HIV cohort studies provides insights into the viral, inflammation, immune activation and antiretroviral therapy related risk factors for HIV-related CVD risk. Yet, an understanding of its pathophysiology remains incomplete. Emerging evidence suggests that gut microbiota (GMB) altered during HIV infection correlates with increased immune activation and disrupted metabolite profiles, but the role of GMB in HIV- related CVD is unknown. Our preliminary data show that in HIV infection, progression of atherosclerosis is associated with higher circulating sCD14, a marker of monocyte activation, and increased tryptophan catabolism. This preliminary work presents two promising candidates linking GMB and CVD risk in HIV infection which we propose to study using integrated “Omics” approaches. In addition to these hypothesis- driven study aims, we will also generate novel hypotheses linking GMB, host immune activation and metabolomics profiles associated with CVD risk. We will leverage the Women’s Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS) >20 year follow-up for biospecimens, atherosclerosis and other CVD measures, and HIV parameters. Our longitudinal semi-annual measures allow us to subset individuals according to long-term HIV treatment, disease progression markers (CD4+ T-cell count, viral load), and comorbidity, with inclusion of matched HIV-uninfected participants. In this project, We will extend our established collaborations with leading labs to gather multi-dimensional data among 400 women and men (~65% of whom are HIV+), including stool GMB metagenomics, serum and cellular inflammation and immunologic markers (sCD14, monocyte transcriptomics), metabolomics, and measures (carotid artery ultrasound imaging over 4 year follow-up). Findings from this intensively studied group will then be extended to a larger sample of 746 women and men with metabolomics and longitudinal atherosclerosis data. In this project, we will have the opportunity to identify immune activation and metabolites underlying the role of GMB in CVD, which may be specific to HIV+ individuals, or accentuated in the setting of HIV.