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

CMV 在 HIV 感染妇女和围产期感染青少年心脏病中的作用

• 批准号: 8915898
• 负责人: DEBORAH Hye SPECTOR
• 金额: $ 71.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915898
• 关键词: 18 year old; Adherence; Adhesions; Affect; Age; Antigens; Arteries; Atherosclerosis; Blood flow; CD4 Positive T Lymphocytes; CD8B1 gene; CX3CL1 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Culture System; Cells; Cellular Immunity; Chronic; Clinical Research; Complication; Cytomegalovirus; Cytomegalovirus Infections; Development; Diabetes Mellitus; Disease; Endothelial Cells; Enterochromaffin Cells; Event; Exhibits; Factor-42; Frequencies; Functional disorder; Generations; HIV; HIV Infections; Health; Heart Diseases; Humoral Immunities; Immune response; Immune system; Immunologics; Individual; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Lead; Lesion; Link; Lymphocyte; Measures; Medical; Modeling; Molecular; Myocardial Infarction; Organism; Pathogenesis; Pattern; Peripheral Blood Mononuclear Cell; Persons; Physiological; Population; Prevention strategy; Research; Research Personnel; Risk; Risk Factors; Role; Site; Smoking; Stroke; System; T cell response; T-Lymphocyte; Thick; Vascular Diseases; Viral; Viral Antigens; Virus; Woman; Youth; antiretroviral therapy; cardiovascular disorder risk; cell injury; cell mediated immune response; chemokine; cofactor; cytokine; fluid flow; hemodynamics; improved; in vitro Model; inflammatory marker; innovation; insight; intima media; macrophage; microbial; novel; novel strategies; pathogen; premature; prevent; public health relevance; research study; response; shear stress; treatment strategy

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.

描述（由申请人提供）： 摘要动脉粥样硬化是导致心肌梗塞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向动脉壁的浸润；然而，导致慢性炎症的事件仍然难以捉摸。 HIV 感染者患 CVD 的风险增加，并且比匹配的未感染者有更严重的亚临床心脏症状。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 之间的联系促使研究人员检查多种感染因子与 HIV 可能的辅助因子之间的关系，以增加 CVD 的风险。在潜在的共同感染病原体中，人类巨细胞病毒（CMV）一直被认为是主要候选病原体。值得注意的是，对 CMV 的免疫反应升高已被多次确定为 HIV 感染者和未感染者中 CVD 的潜在独立危险因素。在这项提议中，我们假设 EC 的感染和对 CMV 的强烈免疫反应（包括 CMV 特异性 T 细胞反应）的产生会导致 HIV 感染者患 CVD 的风险增加。具体目标是确定： 目标 1：确定 HIV 感染者颈动脉内膜中层厚度 (cIMT) 增加与 CMV 免疫反应标志物之间的关系；目标 2：阐明 EC 的 CMV 感染以及不同血流条件下来自 HIV 感染妇女和围产期感染青少年的 CMV 免疫引发和初始 PBMC 的差异粘附如何导致 EC 功能障碍；目标 3：他汀类药物的非降脂功效与抑制 CMV 感染的关联。该提案独特地结合了对 HIV 感染妇女和围产期感染青少年的临床研究，将对 CMV 的免疫反应与早期 CVD 的超声心动图证据联系起来，并确定在原始体外模型中导致心脏结果的发病机制。这一创新模型采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，这些应力密切反映了易患动脉粥样硬化的动脉状况。这项研究将为艾滋病毒感染妇女和围产期感染青少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，并将为改善艾滋病毒感染者心血管健康的治疗和预防策略提供新方法。