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).