Impact of Opiate abuse on HIV-mediated Pulmonary Vascular Remodeling

 描述(由申请人提供)： 随着抗逆转录病毒疗法的出现，人类免疫缺陷病毒(HIV-1)感染者的存活率明显提高，导致非传染性并发症的患病率严重增加。在这方面，最具破坏性的后遗症之一是艾滋病毒感染者的肺动脉高压(HPAH)。静脉吸毒(IVDU)占美国所有新增艾滋病病例的三分之一，已被确定为诊断为HPAH的个人中最常见的危险因素。我们最近的发现表明，海洛因和/或可卡因吸毒者感染HIV的肺组织和暴露于吗啡的猴免疫缺陷(SIV)感染的猕猴肺血管重塑增强，这表明非法药物和HIV-1可能共同作用导致肺动脉病变。此外，SIV感染吗啡处理的猕猴在早期病变中发现凋亡的内皮细胞数量增加，而在晚期丛状病变中观察到通过活跃的内皮免疫缺陷(SIV)细胞增殖而完全闭塞。我们的体外研究结果进一步支持了这一观察结果，与单独使用任何一种处理方法相比，HIV反式转录激活物(TAT)蛋白和吗啡同时处理人肺内皮细胞，促进了细胞的凋亡，随后显着促进了细胞的增殖。根据我们最近的初步发现，我们初步研究的假设是，肺内皮细胞联合暴露于艾滋病毒蛋白(S)和吗啡会诱导自噬，从而促进内皮细胞的增殖和严重的肺血管重构。这一假设将通过追求三个具体目标来检验。在第一个目标中，我们将评估HIV-Tat和吗啡对氧化应激介导的内皮细胞大量自噬的影响。在第二个目标中，我们建议描述选择性自噬在TAT和吗啡介导的促进增殖中的作用。第三个目标将集中在体内研究有或没有吗啡暴露的HIV-1TG大鼠的多环芳烃和自噬。此外，还将测试使用HIV感染的静脉注射吸毒者和SIV感染的吗啡暴露的猕猴的肺标本进行自噬的体外调查。这些研究具有创新性，因为据我们所知，这将是第一次尝试了解自噬在吗啡中的作用与HIV-蛋白质介导的抗凋亡促进增殖之间的潜在联系。这项拟议的研究将加强我们对HPAH发病机制的了解，因此直接响应RFA-HL-14-024(成人和儿童HIV相关心、肺和血液疾病的基础研究)。

 DESCRIPTION (provided by applicant): Improved survival among human immuno-deficiency virus (HIV-1) infected individuals with the advent of antiretroviral therapy has clearly led to serious increase in the prevalence of noninfectious complications. In this regard, one of the most devastating sequelae is the development of pulmonary arterial hypertension in HIV-infected individuals (HPAH). Intravenous drug use (IVDU) accounts for one-third of all new cases of AIDS in the United States and has been identified as the most common risk factor in the individuals diagnosed with HPAH. Our recent findings showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers and in simian immunodeficiency (SIV) -infected macaques exposed to morphine indicate that illicit drugs and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Furthermore, SIV-infected morphine treated macaques were found to have increased number of apoptotic endothelial cells in the early stage lesions, whereas complete occlusion by actively proliferating endothelial simian immunodeficiency (SIV) cells was observed in the advanced stage plexiform lesions. This observation was further supported by our in- vitro findings showing enhanced apoptosis followed by significantly increased proliferation of human pulmonary endothelial cells on simultaneous treatment with HIV- transactivator of transcription (Tat) protein and morphine compared to either treatment alone. Based on our recent preliminary findings, the hypothesis of our pilot study is that the combined exposure of pulmonary endothelial cells to HIV-protein(s) and morphine results in the induction of autophagy that leads to enhanced proliferation of endothelial cells and severe pulmonary vascular remodeling. This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV-Tat and morphine on the oxidative stress mediated bulk autophagy in endothelial cells. In the second aim, we propose to delineate the role of selective autophagy in Tat and morphine mediated enhanced proliferation. Third aim will be focused on in-vivo investigation of PAH and autophagy in HIV-1 Tg rats with or without morphine exposure. In addition, ex-vivo investigation of autophagy using lung specimens from HIV- infected IVDUs and SIV-infected morphine exposed macaques will be tested. These studies are innovative because to the best of our knowledge it will be the first attempt to understand the potential link between the role of autophagy in the morphine and HIV-proteins mediated apoptosis resistant enhanced proliferation. The proposed research will enhance our understanding of the fundamental mechanisms involved in the pathogenesis of HPAH and therefore is directly responsive to RFA-HL-14-024 (Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children).