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不同机制尚不清楚。慢性HIV感染与胃肠道粘膜上皮完整性的丧失和肠道固有层中CD4+T细胞的丧失有关，导致微生物在胃肠道中的移位增加。这项拨款申请的关键假设是，微生物易位导致天然免疫系统的激活，这可能会导致血管系统的炎性损害，导致心血管疾病。目的1通过FDG-PET(评价动脉巨噬细胞活性)和冠状动脉CT血管成像(定量和定性评价冠状动脉粥样硬化斑块)，研究肠上皮完整性和微生物移位与单核细胞和巨噬细胞激活以及通过动脉炎症反应来衡量心血管风险的关系。单核细胞转录转录分析被用来确定HIV感染患者动脉粥样硬化形成的新的生物学途径。为了进一步验证中心假设，在目标2中提出了一项旨在改善肠道上皮完整性和减少微生物易位的干预性研究，以测试这种干预对心血管炎症和单核细胞功能的影响。替杜鲁肽是一种胰升糖素样肽2类似物，对肠道上皮具有已知的营养和抗炎作用，它的干预作用将在艾滋病毒感染者中进行一项随机、双盲安慰剂对照的概念验证试验。需要检验的假设是，肠道上皮完整性的改善将降低肠道对微生物产品的通透性，从而减少TE对单核细胞和巨噬细胞激活的刺激，从而降低FDG-PET测量的动脉壁巨噬细胞活性，降低总体心血管风险。

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.