Multi-omic signatures of gut dysbiosis and cardiovascular comorbidities associated with HIV infection

摘要/摘要 HIV感染与多种心血管合并症相关，包括动脉粥样硬化 心血管疾病和心力衰竭。我们的长期工作专注于亚临床心血管 措施（例如，颈动脉粥样硬化和心功能不全）在妇女的跨部门艾滋病研究 （WIHS）和多中心艾滋病队列研究（MACS）（现为联合队列研究，MWCCS） 提供了对艾滋病毒感染的影响的见解，沿着慢性炎症，免疫激活， 抗逆转录病毒疗法（ART）治疗多种心血管合并症。然而，潜在的发病机制， 这些相互关联的心血管合并症，特别是它们共有的生物学机制， 明白我们在WIHS妇女中的现有工作已经确定了几种肠道细菌和相关宿主 与颈动脉粥样硬化相关的免疫学标记物和微生物代谢物。在本研究中， 我们建议将我们的多组学工作扩展到MWCCS，并将我们的心血管结局扩展到 通过颈动脉超声测量的多种血管和心脏表型（颈动脉斑块， 动脉僵硬度）和超声心动图（左心室[LV]收缩功能障碍、LV舒张功能障碍和 LV纵向应变）。在多达2000名参与者中使用新颖的多方面分析（其中约65%是 HIV+），我们建议应用我们的多组学方法（元基因组学、转录组学、蛋白质组学， 代谢组学），以确定与多种血管和心脏疾病相关的常见肠道微生物改变， 在艾滋病毒感染的背景下，研究这些措施的基本机制。此外，我们将 检查艾滋病毒感染和艾滋病毒特异性因素（例如，长期特异性抗逆转录病毒疗法，持续性病毒血症，CD 4 计数）可能通过改变肠道微生物群和相关的 免疫学和代谢组学特征。这项研究的结果将提高对共同的， 与HIV感染相关的多种心血管合并症的病因重叠。 这些发现还将确定潜在的治疗靶点（例如，微生物群改造）适用于 目前的治疗方法仅部分有效或缺乏这方面的各种心血管疾病， 其他高危人群。

Summary/Abstract HIV infection has been associated with multiple cardiovascular comorbidities, including atherosclerotic cardiovascular disease and heart failure. Our long-standing work focusing on subclinical cardiovascular measures (e.g., carotid artery atherosclerosis and cardiac dysfunction) in the Women’s Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS) (now as a Combined Cohort Study, MWCCS) have provided insights into the effects of HIV infection, along with chronic inflammation, immune activation, and antiretroviral therapy (ART) on multiple cardiovascular comorbidities. However, the underlying pathogenesis of these interrelated cardiovascular comorbidities, and especially their shared biological mechanisms, is not fully understood. Our existing work among WIHS women has identified several gut bacteria and related host immunological markers and microbial metabolites associated with carotid artery atherosclerosis. In this study, we propose to extend our multi-omics work to the MWCCS and expand our cardiovascular outcomes to multiple vascular and cardiac phenotypes measured through carotid artery ultrasound (carotid artery plaque, arterial stiffness) and echocardiography (left ventricular [LV)] systolic dysfunction, LV diastolic dysfunction and LV longitudinal strain). Using a novel multi-faceted analysis among up to 2000 participants (~65% of whom are HIV+), we propose to apply our multi-omics approaches (metagenomics, transcriptomics, proteomics, metabolomics) to identify common gut microbial alterations associated with multiple vascular and cardiac measures and examine their underlying mechanisms in the context of HIV infection. In addition, we will examine how HIV infection and HIV-specific factors (e.g., long-term specific ART, persistent viremia, CD4 counts) may influence cardiovascular phenotypes through alterations in gut microbiota and related immunologic and metabolomic features. Findings from this study will improve understanding of common, overlapping etiologies underlying the multiple cardiovascular comorbidities associated with HIV infection. These findings will also identify potential therapeutic targets (e.g., microbiota modification) applicable to various cardiovascular disorders for which current treatments are only partially effective or lacking in this and other high-risk populations.