Microbial Translocation and HIV-Related Endothelial Dysfunction

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物易位与血管内皮功能障碍之间的关系，从而最终与感染艾滋病毒的患者发生心血管疾病的风险增加之间的关系。众所周知，HIV感染会导致肠道相关淋巴组织(GALT)耗尽和粘膜损伤。这些改变导致肠道微生物产物通过粘膜屏障进入循环的渗透性和移位增加。肠道微生物产物循环水平的增加，如细菌脂多糖(LPS)，已被认为与各种环境中血管功能障碍的各种表现有关，这些表现是通过内皮细胞激活以及局部和全身炎症来实现的。艾滋病毒感染本身，以及用于治疗艾滋病毒感染的抗逆转录病毒疗法(ART)，都与血管内皮功能障碍有关。目前还没有确定可靠的生物标志物，也没有确定这种功能障碍的机制。血管内皮功能障碍为动脉粥样硬化性疾病的发展奠定了基础，并促进了其发展。在感染艾滋病毒的患者中，包括心肌梗死在内的心血管疾病的发病率增加。因此，我们假设肠道微生物产物的移位增加会导致HIV患者的内皮功能障碍。如果发现了相关性，这将证明进一步研究微生物易位和内皮功能障碍之间的联系的病理生理机制是合理的，并建立一个有用的生物标记物作为介入研究的靶点。为了验证我们的中心假设，我们提出了这些具体目标：具体目标1：在HIV感染者中建立微生物易位标志物循环水平与内皮功能障碍之间的关系。我们建议将艾滋病临床试验小组(ACTG 5152s，N=82)和印第安纳大学(IU Study，N=96)完成的研究中的两组具有良好特征的研究对象组合在一起，他们接受了一系列详细的评估，其中包括通过B型超声测量肱动脉的内皮功能(血流介导的扩张，FMD)。使用保存的冰冻标本，将测量循环内毒素、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，以探讨内皮功能障碍与肠道微生物移位、全身免疫激活和炎症的关系。具体目标#2：检查与治疗相关的内皮功能障碍改善与循环肠道微生物标记物水平变化之间的关系。我们假设，与ART相关的微生物易位的减少将导致内皮功能的改善(更大的FMD值)。在ACTG 5152s中，接受ART治疗的受试者内皮功能障碍得到改善。我们将把开始抗逆转录病毒治疗后循环中微生物易位标志物水平的变化与24周时臂FMD的变化联系起来。

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.