Role of CMV in Heart Disease of HIV-Infected Women and Perinatally Infected Youth

描述（由申请人提供）：摘要动脉粥样硬化是导致心肌梗死和中风的心血管疾病（CVD）的主要原因。大量证据表明，动脉粥样硬化是一种炎症性疾病，涉及内皮细胞（EC）功能障碍，以及巨噬细胞和淋巴细胞浸润到动脉壁;然而，负责慢性炎症的事件仍然难以捉摸。艾滋病毒感染者有一个增加的风险心血管疾病，并有更多的先进的亚临床心脏的发现比匹配的未感染的人。此外，越来越多的临床研究表明，在没有任何明显疾病迹象的艾滋病毒感染者中存在血管疾病的早期标志物，包括颈动脉内膜增厚（cIMT）。慢性炎症与CVD的联系使研究人员研究了许多感染因子作为可能的辅助因子与HIV的相关性，以增加CVD的风险。在潜在的共同感染病原体中，人巨细胞病毒（CMV）一直被确定为主要候选者。值得注意的是，对CMV的免疫应答升高已被反复确定为HIV感染和未感染人群中CVD的潜在独立风险因素。在这个建议中，我们假设感染内皮细胞和产生强免疫反应，包括CMV特异性T细胞反应的CMV导致CVD的风险增加的HIV感染者。具体目的是确定：目的1：确定HIV感染者颈动脉内膜中层厚度（cIMT）增加与CMV免疫应答标志物的相关性;目的2：阐明EC的CMV感染以及来自HIV感染女性和围产期感染青年的CMV免疫致敏和幼稚PBMC在不同血流条件下的差异粘附如何导致EC功能障碍;以及目的3：他汀类药物的非降脂益处与抑制CMV感染的相关性该提案独特地结合了对HIV感染妇女和围产期感染青年的临床研究，该研究将对CMV的免疫反应与早期CVD的超声心动图证据相关联，并确定在原始体外模型中负责心脏发现的发病机制。这种创新模型使用多方面的方法来研究在流动和剪切应力条件下HIV，CMV，EC和PBMC之间的相互作用，这些条件密切反映了动脉粥样硬化的易感性。这项研究将为艾滋病毒感染妇女和围产期感染青年的动脉粥样硬化和心血管疾病的发病机制提供新的见解，并将导致新的治疗和预防策略，以改善艾滋病毒感染者的心血管健康。

DESCRIPTION (provided by applicant): ABSTRACT Atherosclerosis is the major cause of cardiovascular disease (CVD) leading to myocardial infarction and stroke. An abundance of evidence indicates that atherosclerosis is an inflammatory disorder involving endothelial cell (EC) dysfunction, and infiltration of macrophages and lymphocytes into the arterial wall; however, the events responsible for the chronic inflammation remain elusive. HIV-infected persons have an increased risk for CVD, and have more advanced subclinical cardiac findings than matched uninfected persons. Moreover, an increasing number of clinical studies has demonstrated the presence of early markers of vascular disease, including carotid intimal thickening (cIMT), in HIV-infected persons without any overt signs of disease. The link of chronic inflammation to CVD has led investigators to examine the association of numerous infectious agents as possible cofactors with HIV to increase the risk for the CVD. Of the potential co- infecting pathogens, human cytomegalovirus (CMV) has consistently been identified as the leading candidate. Of note, elevated immune responses to CMV have been repeatedly identified as potential independent risk factors for CVD in HIV-infected and uninfected populations. In this proposal, we hypothesize that infection of ECs and generation of a strong immune response to CMV including CMV specific T cell responses contribute to the increased risk of CVD in HIV-infected persons. The specific aims are to determine: Aim 1: To identify the association of increased carotid intima-media thickness (cIMT) in HIV-infected persons and markers of CMV immune response; Aim 2: Elucidation of how CMV infection of ECs and differential adhesion of CMV- immunologically primed and naïve PBMCs from HIV-infected women and perinatally-infected youth under different flow conditions contribute to EC dysfunction; and Aim 3: Association of non-lipid lowering benefits of statins with inhibition of CMV infection. This proposal uniquely combines a clinical study of HIV-infected women and perinatally-infected youth that will correlate the immune responses to CMV with echocardiographic evidence of early CVD, and determine the pathogenetic mechanisms responsible for the cardiac findings in an original in vitro model. This innovative model uses a multifaceted approach to study interactions among HIV, CMV, ECs, and PBMCs under conditions of flow and shear stress that closely mirror conditions in arteries susceptible to atherosclerosis. This research will provide novel insights into the pathogenesis of atherosclerosis and CVD in HIV-infected women and perinatally-infected youth, and will lead to new approaches for treatment and prevention strategies to improve cardiovascular health in HIV-infected persons.