Microbial Translocation and HIV-Related Endothelial Dysfunction

微生物易位和 HIV 相关内皮功能障碍

• 批准号: 8012782
• 负责人: Michael Phillip Dube
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012782
• 关键词: AIDS clinical trial group; Area; Bacteria; Biological Markers; Blood Circulation; Blood Tests; Blood Vessels; CD14 gene; Cardiovascular Diseases; Cardiovascular system; Clinical; Development; Disease; Endothelial Cells; Evaluation; Event; Freezing; Functional disorder; Future; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; Heart Diseases; Incidence; Indiana; Individual; Inflammation; Intervention; Intestines; Investigation; Lead; Link; Lipopolysaccharides; Measurement; Measures; Mediating; Myocardial Infarction; Patients; Permeability; Physiological; Research; Ribosomal DNA; Risk; Series; Specimen; Staging; Study Subject; Testing; Ultrasonography; Universities; Vascular Endothelium; antiretroviral therapy; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; clinically relevant; experience; immune activation; improved; microbial; prevent; public health relevance; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): The overall goal of this project is to establish a relationship between translocation of gut microbial products and the dysfunction of the vascular endothelium, and thus ultimately with the increased risk of cardiovascular disease that occurs in patients infected with HIV. HIV infection is known to cause depletion of gut-associated lymphoid tissue (GALT) and mucosal damage. These alterations lead to increased permeability and translocation of gut microbial products across the mucosal barrier and into the circulation. Increased circulating levels of gut microbial products, such as bacterial lipopolysaccharide (LPS), have been linked to various manifestations of vascular dysfunction in a variety of settings via endothelial cell activation and local and systemic inflammation. HIV infection itself, and the antiretroviral therapy (ART) used to treat HIV infection, have been linked to dysfunction of the vascular endothelium. Neither reliable biomarkers nor the mechanisms for this dysfunction have yet been identified. Vascular endothelial dysfunction sets the stage for and promotes the development of atherosclerotic disease. The incidence of cardiovascular disease, including myocardial infarction, is increased in patients infected with HIV. Thus, we hypothesize that increased translocation of gut microbial products leads to endothelial dysfunction in patients with HIV. If an association is found, this will justify further investigation into the pathophysiologic mechanisms underlying the link between microbial translocation and endothelial dysfunction and establish a useful biomarker to target in interventional studies. To investigate our central hypothesis, we propose these Specific Aims: Specific Aim #1: Establish a relationship between circulating levels of microbial translocation markers and endothelial dysfunction in HIV-infected subjects. We propose to combine 2 well-characterized groups of study subjects from investigations completed by the AIDS Clinical Trials Group (ACTG 5152s, N=82) and at Indiana University (IU study, N=96) who underwent a series of detailed evaluations which included measures of endothelial function by B-mode ultrasound of the brachial artery (flow-mediated dilation, or FMD). Using saved frozen specimens, levels of circulating LPS, soluble CD14, and bacterial 16S ribosomal DNA (16S rDNA) will be measured. These biomarkers will be correlated with FMD to investigate the relationship of endothelial dysfunction with gut microbial translocation and systemic immune activation and inflammation. Specific Aim #2: Examine the relationship between treatment-related improvement in endothelial dysfunction and changes in the levels of circulating gut microbial markers. We hypothesize that ART-related decreases in microbial translocation will result in improved endothelial function (greater FMD values). In ACTG 5152s, ART- treated subjects experienced an improvement in endothelial dysfunction. We will correlate changes in circulating levels of microbial translocation markers after initiating ART with changes in brachial FMD at 24 weeks.

描述（由申请人提供）：该项目的总体目标是建立肠道微生物产品的易位与血管内皮的功能障碍之间的关系，因此最终会随着感染HIV患者的心血管疾病风险增加。已知HIV感染会导致肠道相关淋巴组织（GALT）和粘膜损伤的耗竭。这些改变导致肠道微生物产物在粘膜屏障和循环中的易位增加。通过内皮细胞激活以及局部和全身性炎症，各种情况下，循环水平升高的肠道微生物产物（例如细菌脂多糖（LPS））与血管功能障碍的各种表现有关。 HIV感染本身以及用于治疗HIV感染的抗逆转录病毒疗法（ART）与血管内皮的功能障碍有关。尚未确定可靠的生物标志物和这种功能障碍的机制。血管内皮功能障碍为动脉粥样硬化疾病的发展奠定了基础。感染HIV患者的心血管疾病的发生率（包括心肌梗塞）增加。因此，我们假设肠道微生物产物的易位增加会导致HIV患者的内皮功能障碍。如果发现了关联，这将证明对微生物易位和内皮功能障碍之间联系的病理生理机制的进一步研究合理，并为介入研究中的靶向靶向有用。为了研究我们的中心假设，我们提出了这些特定目的：特定目的＃1：在艾滋病毒感染受试者中微生物易位标记水平的循环水平之间建立关系。 We propose to combine 2 well-characterized groups of study subjects from investigations completed by the AIDS Clinical Trials Group (ACTG 5152s, N=82) and at Indiana University (IU study, N=96) who underwent a series of detailed evaluations which included measures of endothelial function by B-mode ultrasound of the brachial artery (flow-mediated dilation, or FMD).使用保存的冷冻标本，将测量循环LP，可溶性CD14和细菌16S核糖体DNA（16S rDNA）的水平。这些生物标志物将与FMD相关，以研究内皮功能障碍与肠道微生物易位和全身免疫激活和炎症的关系。具体目的＃2：检查内皮功能障碍中与治疗相关的改善与循环肠道微生物标记水平的变化之间的关系。我们假设与ART相关的微生物易位下降将导致内皮功能改善（更大的FMD值）。在ACTG 5152中，艺术治疗的受试者经历了内皮功能障碍的改善。我们将在启动ART后与臂FMD的变化在24周后将微生物易位标记的循环水平变化相关联。