The Effects of ART on Platelets and HIV-Associated Thrombosis

ART 对血小板和 HIV 相关血栓形成的影响

基本信息

批准号：
8847014
负责人：
VICENTE PLANELLES
金额：
$ 74.39万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847014
关键词：
Acquired Immunodeficiency Syndrome Acute Address Arterial Fatty Streak Biology Blood Platelets Cardiovascular Diseases Cessation of life Chronic Disease Data Development Disease Epidemiology Eukaryotic Cell Event Exhibits Goals HIV HIV-1 Health Highly Active Antiretroviral Therapy Human Immune Infection Inflammation Mediators Investigation Life Light Medical Megakaryocytes Molecular Morbidity - disease rate Natural History Nucleosides Occupational Exposure Opportunistic Infections Pathogenesis Pathway interactions Patients Phenotype Plasma Platelet Activation RNA-Directed DNA Polymerase Records Research Research Personnel Reverse Transcriptase Inhibitors Risk Scientist Staging Stress T-Lymphocyte Testing Thrombosis Training Translational Repression antiretroviral therapy atherothrombosis base clinically significant experience high risk behavior inhibitor/antagonist innovation insight multidisciplinary non-nucleoside reverse transcriptase inhibitors novel nucleoside analog public health relevance virology

项目摘要

DESCRIPTION (provided by applicant): The advent of antiretroviral therapy (ART) has drastically changed the epidemiology of Acquired Immunodeficiency Syndrome (AIDS). Indeed, human immunodeficiency virus (HIV) patients treated with ART can expect to live for decades and chronic diseases, such as atherothrombosis, are replacing acute infections as important causes of morbidity and death. In the current proposal we unexpectedly demonstrate that megakaryocytes and platelets express endogenous reverse transcriptase (RT) activity, which is specifically blocked by nucleoside analog RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). We also show that inhibition of platelet RT activity leads to the loss of translational repression and the formation of "stress" platelets, which are hyperactive and prone to cause thrombosis. Our robust preliminary data will be leveraged to test the overall hypothesis that ART induces platelet malfunction by directly inhibiting endogenous RT activity in megakaryocytes and platelets, which contributes to the development of atherothrombosis in HIV patients. These aims will be executed by a research team with expertise in platelet biology, virology, thrombosis, and HIV that includes two early stage investigators with outstanding track records. Moreover, this team includes both basic scientists and clinician scientists, providing a strong, multidisciplinary group of investigators that has the experience and training to successfully complete these investigations. Questions proposed by our multi-investigator team are innovative because they explore a novel activity of megakaryocytes and platelets, reverse transcriptase, that may have previously-unrecognized functional consequences in health and disease. They also have immediate clinical significance because new information will be generated regarding the off-target effects of ART that contribute to HIV-related atherothrombosis. Dissecting the mechanisms by which ART regulates reverse transcriptase activity in megakaryocytes and platelets will shed light on how this molecular pathway operates and functions in eukaryotic cells and, in parallel, provide insight into how ART contributes to atherothrombotic events in patients with HIV.

描述（由适用提供）：抗逆转录病毒疗法（ART）的冒险已大大改变了获得的免疫缺陷综合征（AIDS）的流行病学。实际上，接受ART治疗的人类免疫缺陷病毒（HIV）患者可以期望生存数十年，而慢性疾病（例如动脉粥样硬化）正在替代急性感染，因为它是发病率和死亡的重要原因。在当前的提案中，我们出乎意料地证明了巨核细胞和血小板表达内源性逆转录酶（RT）活性，该活性被核苷酸类似物RT抑制剂（NRTIS）和非核苷RT RT抑制剂（NNRTIS）特别阻止。我们还表明，抑制血小板RT活性会导致翻译表达的丧失和“应力”血小板的形成，这些血小板是过度活跃且容易引起血栓形成的。我们的强大初步数据将被利用以检验总体假设，即ART通过直接抑制巨核细胞和血小板的内源性RT活性引起血小板故障，从而有助于HIV患者的动脉粥样硬化。这些目标将由具有血小板生物学，病毒学，血栓形成和艾滋病毒专业知识的研究团队执行，其中包括两个具有出色往绩记录的早期舞台调查员。此外，该团队既包括基本科学家又包括临床。科学家提供了一个强大的多学科研究人员，他们拥有经验和培训，可以成功完成这些投资。我们的多入侵者团队提出的问题具有创新性，因为它们探索了巨核细胞和血小板的新活性，即逆转录酶，这些活动可能在健康和疾病中尚未认识到功能后果。它们也具有直接的临床意义，因为将生成有关有助于与HIV相关的动脉粥样硬化的艺术的脱靶作用的新信息。解剖巨核细胞和血小板中ART调节逆转录酶活性的机制将阐明该分子途径如何在真核细胞中运作和功能，并同时洞悉ART如何为HIV患者的动脉粥样硬化事件贡献。