Immunopathogenesis of HIV-associated pulmonary hypertension

摘要 在与长期HIV感染相关的合并症中，肺动脉高压（PAH） 仍然是一种危及生命的疾病，其特征是肺血管重塑，肺动脉高压， 动脉压和右心衰竭有证据表明，炎症和自身免疫的重要作用 在特发性PAH中，尽管这一概念已在HIV-PAH背景下研究。缺乏 对HIV-PAH发病机制的理解，沿着现有动物模型的不足， 阻碍了新疗法的鉴定和测试。我们开发了一种猿类模型， 艾滋病病毒我们的初步数据表明，炎症，免疫衰老和自身免疫表型 与该模型中肺动脉高压恶化相关。因此，我们假设， HIV-PAH的发展是由慢性免疫激活和免疫应答失调驱动的。 此外，我们假设这种失调的免疫反应部分是由持续的肠道反应驱动的。 微生物易位，并有助于肺动脉平滑肌细胞的过度增殖， 血管组织损伤和纤维化。本提案的总体目标是增进对 HIV-PAH的发病机制，并利用这些信息为开发预防性治疗提供信息， 可以预防或逆转HIV-PAH。我们将测试这些假设，并通过以下方式实现这些目标：1）确定 慢性免疫激活和炎症在非人灵长类动物模型中PAH发生中的作用 2）检查抗逆转录病毒治疗、常规PAH治疗和抗 该模型中的炎症/抗微生物治疗。我们发现SIV感染是PAH的自然原因 与HIV-PAH非常相似，我们已经建立了多种评估疾病进展的模式， 因此，我们处于实现这些目标的独特地位。拟议的研究将增进我们对以下问题的认识： 通过让我们评估疾病过程中每个阶段的宿主免疫反应， 并测试抗病毒和抗炎治疗的功效。这些研究不仅涉及 与HIV-PAH的发展相关的机制，但它们将提供有关以下方面的重要信息： 可能适合于旨在预防和解决血管性心律失常的治疗的时机和目标 损伤、血流动力学改变和右心功能障碍。

ABSTRACT Among the co-morbidities associated with long-term HIV infection, pulmonary arterial hypertension (PAH) remains a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure and right heart failure. Evidence suggests a prominent role for inflammation and autoimmunity in idiopathic PAH, though this concept has been under studied in the context of HIV-PAH. Lack of understanding of the pathogenesis of HIV-PAH, along with deficiencies of available animal models, greatly impede identification and testing of new therapies. We have developed a simian model that closely mimics HIV-PAH. Our preliminary data indicate that inflammation, immunosenescence and autoimmune phenotypes are associated with worse pulmonary hypertension in this model. We therefore hypothesize that the development of HIV-PAH is driven by chronic immune activation and dysregulated immune responses. Additionally, we hypothesize that this dysregulated immune response is driven in part by persistent gut microbial translocation, and contributes to hyper-proliferation of pulmonary arterial smooth muscle cells, vascular tissue damage and fibrosis. Overall goals of this proposal are to improve the understanding of the pathogenesis of HIV-PAH and to use this information to inform the development of adjunctive therapies that will prevent or reverse HIV-PAH. We will test these hypotheses and address these goals by 1) determining the role of chronic immune activation and inflammation on the development of PAH in a non-human primate model of HIV-PAH and 2) examining the effectiveness of anti-retroviral therapy, conventional PAH therapy and anti- inflammatory/anti-microbial therapy in this model. We have found that SIV infection is a natural cause of PAH that closely mimics HIV-PAH and we have established multiple modalities of evaluating disease progression, thus we are uniquely positioned to address these goals. The proposed studies will advance our knowledge of disease progression by allowing us to evaluate host immune responses at each stage of the disease process and test efficacy of anti-viral and anti-inflammatory therapies. These studies will not only address the mechanisms associated with the development of HIV-PAH, but they will provide critical information regarding the timing and targets that may be amenable to therapies aimed at both prevention and resolution of vascular damage, hemodynamic alterations and right heart dysfunction.