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

HIV CVD风险的综合分析：肠道菌群、免疫功能和代谢物

• 批准号: 9476675
• 负责人: ROB KNIGHT
• 金额: $ 87.64万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476675
• 关键词: Atherosclerosis; Bile Acids; Blood; CD14 gene; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Plaques; Catabolism; Cell Count; Cohort Studies; Collaborations; Communities; Comorbidity; Data; Development; Disease Progression; Feces; Functional disorder; Genes; HIV; HIV Infections; Immunity; Immunologic Markers; Individual; Inflammation; Innate Immune System; Interleukin-16; Intervention; Kynurenine; Link; Measures; Metabolic Pathway; Metagenomics; Participant; Pathway Analysis; Pathway interactions; Preventive Intervention; Prospective Studies; Public Health; Risk Factors; Role; Sampling; Serum; Serum Markers; Specimen; Testing; The Multicenter AIDS Cohort Study; Toll-like receptors; Tryptophan; Ultrasonography; Up-Regulation; Urine; Validation; Viral; Viral Load result; Volatile Fatty Acids; Woman; Women’s Interagency HIV Study; Work; antiretroviral therapy; base; cardiovascular disorder risk; cohort; design; dysbiosis; follow-up; gene function; gut microbiota; immune activation; immune function; inflammatory marker; innovation; insight; intimal medial thickening; men; metabolic profile; metabolomics; monocyte; network models; novel; pathogen; progression marker; public health relevance; receptor; transcriptomics; trimethyloxamine

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.

摘要/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 HIV相关心血管疾病风险的抗逆转录病毒治疗相关危险因素。然而，对其病理生理学的了解 仍然不完整。新的证据表明，在HIV感染过程中肠道微生物区系(GMB)发生了变化 与免疫激活增强和代谢产物谱紊乱有关，但GMB在HIV- 相关的CVD尚不清楚。我们的初步数据显示，在艾滋病毒感染中，动脉粥样硬化的进展是 与单核细胞活化的标志--循环中的sCD14升高和色氨酸增加有关 分解代谢。这项初步工作提出了两个有希望的候选对象，将绿色荧光蛋白与艾滋病毒的心血管疾病风险联系起来 我们建议使用综合的“OMICS”方法来研究这种感染。除了这些假设之外-- 推动研究目标，我们还将产生新的假说，将GMB、宿主免疫激活和 与心血管疾病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)和对生物制品、动脉粥样硬化和其他疾病的20年随访 心血管疾病测量和艾滋病毒参数。我们每半年一次的纵向衡量标准允许我们对个人进行细分 根据长期的艾滋病毒治疗，疾病进展标志(CD4+T细胞计数，病毒载量)，以及 共病，包括匹配的未感染艾滋病毒的参与者。在这个项目中，我们将扩展我们的 与领先实验室建立合作，在400名女性和男性(约65%)中收集多维数据 其中HIV+)，包括粪便GMB元基因组学、血清和细胞炎症和免疫学 标记物(sCD14、单核细胞转录组)、代谢组学和测量(颈动脉超声成像 4年以上的随访)。来自这一深入研究小组的发现将扩展到更大的样本 746名女性和男性的代谢组学和纵向动脉粥样硬化数据。在这个项目中，我们将拥有 有机会确定GMB在心血管疾病中潜在的免疫激活和代谢物，这可能是 特定于艾滋病毒+的个人，或在艾滋病毒的背景下被强调。