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 我们先前从事HIV队列研究的工作提供了有关病毒，炎症，免疫激活和 与HIV相关CVD风险的抗逆转录病毒疗法相关的风险因素。然而，对其病理生理学的理解 仍然不完整。新兴的证据表明，肠道菌群（GMB）在HIV感染期间发生了改变 与免疫激活增加和代谢物谱的破坏相关，但GMB在HIV-中的作用 相关的CVD是未知的。我们的初步数据表明，在HIV感染中，动脉粥样硬化的进展是 与较高的循环SCD14（单核细胞激活的标志物）相关，并增加了色氨酸 分解代谢。这项初步工作提出了两名诺言候选人，将GMB和CVD风险联系起来 我们建议使用综合“ OMIC”方法研究的感染。除了这些假设 - 驱动的研究目的，我们还将产生与GMB，宿主免疫激活和 与CVD风险相关的代谢组学轮廓。我们将利用妇女的机构间艾滋病毒研究（WIHS） 和多中心艾滋病队列研究（MAC）>生物测量，动脉粥样硬化和其他的20年随访 CVD测量和HIV参数。我们的纵向半年度测量使我们能够将个体子集 根据长期HIV治疗，疾病进展标志物（CD4+ T细胞计数，病毒载荷）和 合并症，包括匹配的HIV未感染参与者。在这个项目中，我们将扩展我们的 与领先的实验室建立了合作，以收集400名男性和男性的多维数据（约65％ 其中包括HIV+），包括粪便GMB宏基因组学，血清和细胞注射和免疫学 标记（SCD14，单核细胞转录组学），代谢组学和测量（颈动脉超声成像 超过4年的随访）。然后，该强度研究组的发现将扩展到更大的样本 746名具有代谢组学和纵向动脉粥样硬化数据的男性和男性。在这个项目中，我们将拥有 鉴定GMB在CVD中作用的基础的免疫激活和代谢产物的机会，这可能是 特定于艾滋病毒+个体，或在艾滋病毒的情况下强调。