Viral Protein Mediators of HIV-Related Pulmonary Hypert*

描述(申请人提供)：肺动脉高压(PAH)涉及肺血管的病理性重塑，经常导致严重的残疾和死亡。感染艾滋病毒的患者发生PAH的几率高于预期。这项提案将特别关注在感染HIV-1的患者中表达的病毒基因产物使宿主容易患上PAH的机制。此外，这项建议将探索目前用于治疗HIV-1的高效逆转录病毒疗法(HAART)对这些机制的调节作用。Tat是一种重要的调控蛋白，负责HIV-1转录激活。明确TAT如何单独或与体内和体外HIV+患者血清中升高的其他肽因子一起调节内皮细胞功能以促进PAH的发展，是该提案的一个重点。重要的是，感染艾滋病毒的患者通常与人类疱疹病毒-8(HHV-8)混合感染。已知HHV-8定位于肺内皮细胞，与HIV相关性肺动脉高压(HRPH)和特发性肺动脉高压(IPAH)相关，并表达一种病毒G蛋白偶联受体(VGPCR)，可诱导血管增生性疾病。在这项提案中要检验的中心假设是，HHV-8vGPCR与TAT一起易使个人患上HRPH。根据本RFA的指导，该方法将研究HHV-8vGPCR、TAT和HAART对人类来源的肺血管内皮细胞和平滑肌细胞的影响。体外研究结果的生物学意义将使用PAH的小鼠低压低氧模型在体内进行评估，因为艾滋病患者会出现低氧应激。这项建议汇集了4名由美国国立卫生研究院资助的研究人员的合作专业知识，以及与血管生成、血管生物学和药理学相关的互补技能和经验，以解决这一重要的临床疾病。针对这些特定目的的实验将确定vGPCR、TAT和HAART药物在HRPR发展中的作用，并促进我们对这种致命疾病的发病机制的理解，这反过来将最终导致对PAH的更有效的治疗。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) involves pathological remodeling of the lung vasculature and frequently results in significant disability and death. Patients infected with HIV have a higher than expected incidence of PAH. This proposal will focus specifically on mechanisms through which viral gene products expressed in patients infected with HIV-1 predispose the host to develop PAH. In addition, this proposal will explore the modulatory effects of current highly active retroviral therapy (HAART) for the treatment of HIV-1 on these mechanisms. Tat is an essential regulatory protein responsible for transcriptional activation of HIV-1. Defining how Tat modulates endothelial cell function towards the development of PAH, alone or together with other peptide factors elevated in the serum of HIV+ patients, in vitro and in vivo, is a focus of this proposal. Importantly, patients infected with HIV are commonly co-infected with human herpesvirus-8 (HHV-8). HHV-8 is known to localize to the lung endothelium, is associated with both HIV-related pulmonary hypertension (HRPH) and idiopathic pulmonary artery hypertension (iPAH), and expresses a viral G-protein coupled receptor (vGPCR) that induces angioproliferative disease. The central hypothesis to be tested in this proposal is that HHV-8 vGPCR togther with Tat predispose an individual to develop HRPH. In keeping with the directives of this RFA, the approach will study the effects of HHV-8 vGPCR, Tat, and HAART on pulmonary vascular endothelial cells and smooth muscle cells derived from humans. The biological significance of findings from the in vitro studies will be evaluated in vivo using a murine hypobaric hypoxia model of PAH because hypoxic stress occurs in patients with AIDS. This proposal brings together the collaborative expertise of 4 NIH-funded investigators, with complementary skills and experience pertaining toangiogenesis, vascular biology, and pharmacology to address this important clinical malady. The experiments to address these Specific Aims will define the role of vGPCR, Tat and HAART drugs in the development of HRPR and advance our understanding of the pathogenesis of this fatal disease, which in turn will eventuate in more effective treatments for PAH.