Targeting GI Epithelial Integrity to Improve Arterial Inflammation in HIV

描述（申请人提供）：心血管疾病在hiv感染患者中非常普遍，然而hiv感染患者动脉粥样硬化性疾病发展的独特机制尚不清楚。慢性HIV感染与胃肠道粘膜上皮完整性丧失和肠固有层CD4+ t细胞丧失相关，导致胃肠道微生物易位增加。这项资助申请的关键假设是，微生物易位引起先天免疫系统的激活，从而诱导血管的炎症损伤，导致心血管疾病。目的1旨在研究肠道上皮完整性和微生物易位与单核细胞和巨噬细胞活化的关系，以及通过FDG-PET（评估动脉巨噬细胞活性）和冠状动脉计算机断层血管造影（定量和定性评估冠状动脉粥样硬化斑块）测量动脉炎症的心血管风险。在单核细胞转录组学分析提出，以确定新的生物途径动脉粥样硬化在hiv感染患者。为了进一步验证中心假设，Aim 2提出了一项改善肠道上皮完整性和减少微生物易位的介入研究，以测试这种干预对心血管炎症和单核细胞功能的影响。teduglutide是一种胰高血糖素样肽2类似物，已知对肠上皮具有营养和抗炎作用，将在hiv感染者的随机、双盲、安慰剂对照的概念验证试验中进行研究。待验证的假设是，肠道上皮完整性的改善会降低肠道对微生物产物的渗透性，从而减少对单核细胞和巨噬细胞活化的刺激，从而降低FDG-PET测量的动脉壁巨噬细胞活性，降低整体心血管风险。

DESCRIPTION (provided by applicant): Cardiovascular disease is highly prevalent among HIV-infected patients, however the distinct mechanisms of atherosclerotic disease development in HIV-infected patients are yet unknown. Chronic HIV infection is associated with loss of gastrointestinal mucosal epithelial integrity and loss of CD4+ T-cells in the intestinal lamina propria, leading to increased microbial translocation across the gastrointestinal tract. The key hypothesis of this grant application is that microbial translocation causes activation of the innat immune system which can induce inflammatory damage in the vasculature, leading to cardiovascular disease. Aim 1 seeks to study the relationships of intestinal epithelial integrity and microbial translocation to monocyte and macrophage activation and to cardiovascular risk measured by arterial inflammation via FDG-PET (to assess arterial macrophage activity) and coronary cardiac computed tomography angiography (to assess coronary atherosclerotic plaque quantitatively and qualitatively). Transcriptomic analyses in monocytes are proposed to identify novel biological pathways of atherogenesis in HIV-infected patients. To further test the central hypothesis, an interventional study is proposed in Aim 2 to improve the gut epithelial integrity and reduce microbial translocation in order to test effects of such an intervention on cardiovascular inflammation and monocyte function. The intervention of teduglutide, a glucagon-like peptide 2 analog with known trophic and anti-inflammatory effects on the intestinal epithelium, will be investigated in a randomized, double-blind placebo-controlled proof of concept trial in HIV-infected individuals. The hypothesis to be tested is that improvement of gut epithelial integrity will decrease intestinal permeability to microbial products, thus decreasing te stimulus for monocyte and macrophage activation, and therefore decrease macrophage activity in the arterial wall measured by FDG-PET and reduce overall cardiovascular risk.