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Immunopathogenesis of HIV-associated pulmonary hypertension

HIV相关肺动脉高压的免疫发病机制

基本信息

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
项目类别：
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

项目摘要

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.

摘要