Immunopathogenesis of HIV-associated pulmonary hypertension

HIV相关肺动脉高压的免疫发病机制

• 批准号: 9370162
• 负责人: Karen A Norris
• 金额: $ 74.97万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-23 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370162
• 关键词: Address; Aging; Animal Model; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antibiotics; Autoimmune Process; Autoimmune Responses; Autoimmunity; Blood Vessels; Cardiovascular Diseases; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Complication; Data; Dementia; Development; Disease; Disease Progression; Effectiveness; Evaluation; Fibrosis; Functional disorder; Goals; HIV; HIV Infections; HIV Seropositivity; HIV therapy; Health; Heart failure; Homeostasis; Human; Immune; Immune response; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Knowledge; Life; Life Expectancy; Longitudinal Studies; Lung; Macaca; Microbe; Minocycline; Modality; Modeling; Myocardial dysfunction; Pathogenesis; Pathology; Pathway interactions; Phenotype; Positioning Attribute; Prevalence; Prevention; Primates; Process; Property; Pulmonary Hypertension; Research; Resolution; Risk; Rodent Model; Role; SIV; Smooth Muscle Myocytes; Staging; Terminal Disease; Testing; Tetracyclines; Therapeutic; Time; Tissues; Treatment Efficacy; Vascular remodeling; Virus Diseases; anti-viral efficacy; antimicrobial; base; comorbidity; conventional therapy; efficacy testing; exhaustion; hemodynamics; immune activation; immunosenescence; improved; in vivo; microbial; nonhuman primate; novel therapeutics; pressure; prevent; primary pulmonary hypertension; pulmonary arterial hypertension; response; senescence; tadalafil

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.

抽象的 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发挥着重要作用 在特发性 PAH 中，尽管这一概念已在 HIV-PAH 的背景下进行了研究。缺乏 对 HIV-PAH 发病机制的了解以及现有动物模型的缺陷，极大地促进了对 HIV-PAH 发病机制的了解 阻碍新疗法的鉴定和测试。我们开发了一种非常模仿的猿猴模型 HIV-PAH。我们的初步数据表明炎症、免疫衰老和自身免疫表型 在该模型中与更严重的肺动脉高压相关。因此我们假设 HIV-PAH 的发展是由慢性免疫激活和免疫反应失调驱动的。 此外，我们假设这种失调的免疫反应部分是由持续的肠道驱动的 微生物易位，并导致肺动脉平滑肌细胞过度增殖， 血管组织损伤和纤维化。该提案的总体目标是提高对 HIV-PAH 的发病机制，并利用这些信息为辅助疗法的开发提供信息 将预防或逆转 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 在非人类灵长类动物模型中，慢性免疫激活和炎症对 PAH 发展的作用 HIV-PAH 的研究和 2) 检查抗逆转录病毒治疗、常规 PAH 治疗和抗-PAH 治疗的有效性 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方法， 因此，我们在实现这些目标方面处于独特的地位。拟议的研究将增进我们的知识 通过使我们能够评估疾病过程每个阶段的宿主免疫反应来疾病进展 并测试抗病毒和抗炎疗法的功效。这些研究不仅将解决 与 HIV-PAH 发展相关的机制，但它们将提供有关以下方面的关键信息： 可能适合旨在预防和解决血管性病变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。