Role of tetherin in HIV-associated thromsosis

Tetherin 在 HIV 相关血栓形成中的作用

• 批准号: 8925642
• 负责人: SANJAY B. MAGGIRWAR
• 金额: $ 55.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925642
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Advanced Development; Arterial Fatty Streak; Arteries; Basic Science; Biology; Blood Circulation; Blood Platelets; Cell surface; Cells; Chronic; Chronic Disease; Clinical; Clinical Research; Collaborations; Cytoplasmic Tail; Data; Development; Disease; Down-Regulation; Event; Exhibits; Exposure to; Foundations; Goals; HIV; Health; Heart Diseases; Hematological Disease; Individual; Infection; Inflammation; Inflammation Mediators; Investigation; Learning; Link; Lung diseases; Lysine; Mammalian Cell; Molecular; Morbidity - disease rate; Mus; Mutation; N-terminal; Pathway interactions; Patients; Phosphatidylserines; Polyubiquitination; Production; Recording of previous events; Research; Research Infrastructure; Research Personnel; Resistance; Risk; Role; Scientist; Serine; Stimulus; Testing; Threonine; Thromboplastin; Thrombosis; Thrombus; Translations; Universities; Viral Proteins; Virus; Virus Diseases; abstracting; antiretroviral therapy; atherothrombosis; base; disorder risk; experience; human subject; in vitro Model; in vivo; innovation; insight; monocyte; mortality; mouse model; multicatalytic endopeptidase complex; multidisciplinary; novel; novel therapeutic intervention; prevent; public health relevance; response; virology

 DESCRIPTION (provided by applicant): Widespread use of combination antiretroviral therapy (cART) has led to increased survival of Human Immunodeficiency Virus (HIV)-infected patients. As a result, chronic diseases are increasingly replacing acute infections as important causes of morbidity and mortality. One of these chronic diseases is atherothrombosis, the underlying mechanisms of which are not fully elucidated. Here, we demonstrate that monocytes and platelets from HIV-infected, cART-treated individuals exhibit reduced levels of the host restriction factor Tetherin BST-2/CD317), and that Tetherin loss is induced by exposure of healthy cells to the viral protein Tat, and to other inflammatory mediators of cellular origin, via proteasome-dependent mechanisms. We also show that over-expression of degradation-resistant Tetherin, which contains a S3T4S5 substitution mutation, in monocytes causes sequestration of fully formed microparticles (MPs) on the cell surface. These findings will be leveraged to test the overall hypothesis that HIV promotes thrombosis via Tetherin-dependent release of cellular MPs. Briefly, we will examine the loss of Tetherin and associated release of MPs by employing in vitro models of HIV infection (Aim 1), novel mouse models of HIV-associated thrombosis in vivo (Aim 2), and prospectively determine how these events are linked in HIV patients receiving cART (Aim 3). These studies will bring together four established investigators and two emerging investigators with proven expertise in virology, platelet/monocyte biology, MPs, thrombosis, and HIV clinical research. Importantly, proposed studies will leverage research infrastructure offered by the University of Rochester Center for AIDS Research (UR-CFAR). Our studies contain great potential for clinical translation. Changes in Tetherin expression will be directly tested in human subjects and linked with atherothrombosis. As such, revealing the mechanisms through which HIV and cART regulate the production of microparticles in monocytes and platelets will provide a critical basic science foundation so as to understand how these molecular pathways function in mammalian cells, while providing insight into how HIV triggers atherothrombotic events in patients who are or are not receiving cART. In summary, our proposal is discovery-oriented, translational, and is responsive to the goals of RFA (RFA-HL- 14-024).

 描述(由申请人提供)：联合抗逆转录病毒疗法(CART)的广泛使用提高了人类免疫缺陷病毒(HIV)感染患者的存活率。因此，慢性病越来越多地取代急性感染，成为发病率和死亡率的重要原因。动脉粥样硬化血栓形成是这些慢性疾病之一，其潜在机制尚未完全阐明。在这里，我们证明了来自HIV感染、CART治疗的个体的单核细胞和血小板表现出宿主限制因子Tetherin BST-2/CD317水平的降低，并且Tetherin丢失是由健康细胞暴露于病毒蛋白Tat和其他细胞来源的炎症介质通过 蛋白酶体依赖机制。我们还表明，在单核细胞中过表达耐降解的Tetherin(包含S3T4S5替换突变)会导致完全形成的微粒(MPS)隔离在细胞表面。这些发现将被用来检验HIV通过Tetherin依赖的细胞MPS释放促进血栓形成的总体假设。简而言之，我们将通过使用HIV体外感染模型(AIM 1)、体内HIV相关血栓形成的新小鼠模型(AIM 2)来检查Tetherin的丢失和相关的MPS的释放，并前瞻性地确定这些事件在接受CART的HIV患者中是如何联系的(Aim 3)。这些研究将汇集四名老牌研究人员和两名新兴研究人员，他们在病毒学、血小板/单核细胞生物学、MPS、血栓形成和艾滋病毒临床研究方面拥有成熟的专业知识。重要的是，拟议的研究将利用罗切斯特大学艾滋病研究中心(UR-CFAR)提供的研究基础设施。我们的研究蕴含着巨大的临床翻译潜力。Tetherin表达的变化将直接在受试者身上进行测试，并与动脉粥样硬化血栓形成有关。因此，揭示HIV和CART调节单核细胞和血小板中微粒产生的机制将提供关键的基础科学基础，以便了解这些分子途径如何在哺乳动物细胞中发挥作用，同时为HIV如何在接受或不接受CART的患者中触发动脉粥样硬化血栓事件提供洞察力。总而言之，我们的提案是面向发现的、可翻译的，并响应了RFA的目标(RFA-HL-14-024)。