The Effects of ART on Platelets and HIV-Associated Thrombosis

 描述（由申请人提供）：抗逆转录病毒疗法（ART）的出现极大地改变了获得性免疫缺陷综合征（AIDS）的流行病学。事实上，接受抗逆转录病毒疗法治疗的人类免疫缺陷病毒（艾滋病毒）患者可以预期活几十年，而动脉粥样硬化血栓形成等慢性疾病正在取代急性感染，成为发病和死亡的重要原因。在目前的提案中，我们出乎意料地证明，巨核细胞和血小板表达内源性逆转录酶（RT）活性，这是特异性阻断核苷类似物RT抑制剂（NRTI）和非核苷RT抑制剂（NNRTI）。我们还表明，血小板RT活性的抑制导致翻译抑制的丧失和“应激”血小板的形成，这是过度活跃的，容易引起血栓形成。我们强大的初步数据将被用来测试的总体假设，ART诱导血小板功能障碍，直接抑制巨核细胞和血小板，这有助于发展动脉粥样硬化血栓形成的HIV患者的内源性RT活性。这些目标将由一个在血小板生物学、病毒学、血栓形成和艾滋病毒方面具有专业知识的研究小组执行，其中包括两名具有出色记录的早期研究人员。此外，该团队包括基础科学家和临床科学家，提供了一个强大的，多学科的研究小组，具有成功完成这些研究的经验和培训。我们的多研究者团队提出的问题是创新的，因为他们探索了巨核细胞和血小板逆转录酶的一种新活性，这种活性可能对健康和疾病产生以前未被认识的功能性后果。它们也具有直接的临床意义，因为将产生关于ART的脱靶效应的新信息，这些脱靶效应有助于HIV相关的动脉粥样硬化血栓形成。剖析ART调节巨核细胞和血小板中逆转录酶活性的机制，将揭示这种分子途径在真核细胞中如何运作和发挥作用，并同时深入了解ART如何促进HIV患者的动脉粥样硬化血栓形成事件。

 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.