Immune Mechanisms of HIV-associated COPD

HIV相关慢性阻塞性肺病的免疫机制

• 批准号: 9116276
• 负责人: Gregory D Kirk
• 金额: $ 69.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116276
• 关键词: Acute Pneumonia; Address; Apoptosis; Behavioral; Biological; Blood; Blood specimen; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; CD8B1 gene; Cause of Death; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical Management; Clinical Research; Collaborations; Collection; Consequences of HIV; Data; Databases; Development; Diffusion; Disease; Disease Marker; Dyspnea; Etiology; Fibrosis; HIV; HIV Infections; HIV Seropositivity; Health; Heterogeneity; Hospitalization; Immune; Immunity; Immunology; Impairment; Individual; Interleukin-10; Longitudinal Studies; Lung; Lung diseases; Morbidity - disease rate; Mucous Membrane; Obstruction; Participant; Patients; Persons; Phenotype; Physiological; Plasma; Population; Population Research; Predisposition; Prevalence; Production; Publishing; Pulmonary Emphysema; Quality of life; Recruitment Activity; Regulatory T-Lymphocyte; Reporting; Research Infrastructure; Research Personnel; Resources; Respiratory physiology; Risk; Risk Factors; Sampling; Secondary to; Series; Severities; Severity of illness; Smoker; Smoking; Spirometry; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Tobacco use; Viral Load result; Viremia; Virus Replication; Visit; airway inflammation; base; clinical investigation; cohort; cytotoxicity; disease phenotype; exhaustion; follow-up; high risk; illicit drug use; immune activation; improved; mortality; multidisciplinary; outcome forecast; prospective; research study; respiratory; response; study population; therapy development

DESCRIPTION (provided by applicant): HIV-infected persons appear to be at higher risk for chronic obstructive pulmonary disease (COPD), although the clinical manifestations and underlying mechanisms of HIV-associated COPD remain unclear. The ongoing Study of HIV Infection in the Etiology of Lung Disease (SHIELD) cohort has recruited >2,000 participants to prospectively evaluate how HIV infection may enhance susceptibility to COPD. SHIELD data suggest that poorly controlled plasma HIV viremia accelerates lung function decline. Further, HIV-associated COPD is characterized by CD4+ T cell depletion occurring to a greater extent in the lung mucosa than in the periphery. Based on these findings, our central hypothesis is that the development and clinical manifestations of HIV- associated COPD are driven, at least in part, by HIV viral replication, CD4+ T cell depletion and CD8+ T cell immune activation in the lung mucosa. In Aim 1, we identify and differentiate clinical, physiologic, and radiographic COPD phenotypes in HIV-infected compared to uninfected persons. Then, we prospectively follow these participants to define the clinical and patient-reported consequences of COPD phenotypes. In Aim 2, we determine whether the presence and severity of HIV-associated COPD is correlated with depletion of lung CD4+ T cells. In Aim 3, we test the hypothesis that lung CD4+ depletion and dysregulation is due to HIV infection and replication. In Aim 4, we examine whether there is increased lung CD8+ T cell immune activation in HIV-associated COPD, due at least in part, to loss of CD4+ T cell regulatory mechanisms. Our multidisciplinary team of investigators provides clinical and research expertise in HIV, pulmonary diseases, and immunology, and have an established track record of productive collaboration in HIV and COPD. SHIELD provides an ideal study population and research infrastructure to perform these clinical and mechanistic studies. In summary, this proposal directly addresses critical gaps in our understanding of the clinical spectrum and consequences of HIV-associated COPD and will identify key biologic mechanisms contributing to the disease. Findings will inform the clinical management and development of interventions targeting HIV- associated COPD, and may also inform broader strategies for COPD in non-HIV infected populations.

描述（由申请人提供）：艾滋病毒感染者似乎面临慢性阻塞性肺疾病（COPD）的风险，尽管临床表现和与HIV相关的COPD的基本机制尚不清楚。正在进行的对HIV感染在肺病病因（SHIELD）队列中的研究已招募了> 2,000名参与者，以预期评估HIV感染如何增强对COPD的易感性。屏蔽数据表明，控制不良的血浆HIV病毒血症会加速肺功能下降。此外，与外周相比，与HIV相关的COPD的特征在于肺粘膜中发生的CD4+ T细胞耗竭。基于这些发现，我们的中心假设是，与HIV相关COPD的发育和临床表现至少部分通过HIV病毒复制，CD4+ T细胞耗竭和CD8+ T细胞免疫激活在肺粘膜中驱动。在AIM 1中，与未感染的人相比，我们鉴定并区分了HIV感染的HIV感染的临床，生理和放射线COPD表型。然后，我们前瞻性地跟随这些参与者来定义COPD表型的临床和患者报告的后果。在AIM 2中，我们确定与HIV相关的COPD的存在和严重程度是否与肺CD4+ T细胞的消耗相关。在AIM 3中，我们检验了以下假设：肺CD4+耗竭和失调是由于HIV感染和复制引起的。在AIM 4中，我们检查了与CD4+ T细胞调节机制的丧失，在与HIV相关的COPD中是否增加了肺CD8+ T细胞免疫激活。我们的多学科研究人员团队提供了艾滋病毒，肺部疾病和免疫学方面的临床和研究专业知识，并在艾滋病毒和COPD中具有既定的生产性合作记录。 Shield提供了理想的研究人群和研究基础设施，以进行这些临床和机械研究。总而言之，该提案直接解决了我们对HIV相关COPD的临床光谱和后果的关键差距，并将确定有助于该疾病的关键生物学机制。调查结果将为针对HIV相关COPD的干预措施的临床管理和发展提供信息，并可能为非HIV感染人群中的COPD提供更广泛的策略。