Role of tetherin in HIV-associated thromsosis

Tetherin 在 HIV 相关血栓形成中的作用

基本信息

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
项目类别：
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

项目摘要

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）感染患者的生存率，因此，慢性疾病越来越多地取代急性感染，成为发病和死亡的重要原因。这些慢性疾病之一是动脉粥样硬化血栓形成，其潜在机制尚未完全阐明。在这里，我们证明感染艾滋病毒的单核细胞和血小板，经过 cART 治疗的个体表现出宿主限制因子 Tetherin BST-2/CD317 水平降低，并且 Tetherin 损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诱导的，通过我们还表明，单核细胞中含有 S3T4S5 取代突变的抗降解 Tetherin 的过度表达会导致完全形成的微粒 (MP) 被隔离在细胞表面。这些发现将用于测试整体情况。 HIV 通过 Tetherin 依赖性细胞 MP 释放促进血栓形成的假设简而言之，我们将通过采用 HIV 感染的体外模型来检查 Tetherin 的损失和相关的 MP 释放。（目标 1）、体内 HIV 相关血栓形成的新型小鼠模型（目标 2），并前瞻性地确定这些事件在接受 cART 的 HIV 患者中如何关联（目标 3）。这些研究将汇集四名成熟的研究人员和两名新兴的研究人员。拥有病毒学、血小板/单核细胞生物学、MP、血栓形成和艾滋病毒临床研究方面经过验证的专业知识。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。 Tetherin 表达的变化将在人类受试者中直接进行测试，并与动脉粥样硬化血栓形成相关，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为研究提供重要的基础科学基础。了解这些分子途径如何在哺乳动物细胞中发挥作用，同时深入了解 HIV 如何在接受或未接受 cART 的患者中引发动脉粥样硬化血栓事件。总之，我们的建议是发现导向的、转化性的，并且是响应性的。 RFA 的目标 (RFA-HL-14-024)。