Immune Mechanisms of HIV-associated COPD

HIV相关慢性阻塞性肺病的免疫机制

• 批准号: 8638392
• 负责人: Gregory D Kirk
• 金额: $ 67.8万
• 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/8638392
• 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; Clinical Trials; Collaborations; Collection; Consequences of HIV; Data; Databases; Development; Diffusion; Disease; Disease Marker; Drug usage; Dyspnea; Etiology; Fibrosis; HIV; HIV Infections; HIV Seropositivity; Heterogeneity; Hospitalization; Illicit Drugs; 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; Viral Load result; Viremia; Visit; airway inflammation; base; cohort; cytotoxicity; disease phenotype; exhaustion; follow-up; high risk; immune activation; improved; mortality; multidisciplinary; outcome forecast; prospective; public health relevance; research study; respiratory; response; 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）：尽管 HIV 相关 COPD 的临床表现和潜在机制仍不清楚，但 HIV 感染者似乎具有较高的慢性阻塞性肺疾病 (COPD) 风险。正在进行的肺病病因中 HIV 感染研究 (SHIELD) 队列已招募了超过 2,000 名参与者，以前瞻性评估 HIV 感染如何增加 COPD 的易感性。 SHIELD 数据表明，血浆 HIV 病毒血症控制不佳会加速肺功能下降。此外，HIV相关的COPD的特征是CD4+T细胞耗竭在肺粘膜中发生的程度比在外周中更大。基于这些发现，我们的中心假设是，HIV相关COPD的发展和临床表现至少部分是由肺粘膜中的HIV病毒复制、CD4+T细胞耗竭和CD8+T细胞免疫激活驱动的。在目标 1 中，我们识别并区分 HIV 感染者与未感染者的临床、生理和影像学 COPD 表型。然后，我们前瞻性地跟踪这些参与者，以确定 COPD 表型的临床和患者报告的后果。在目标 2 中，我们确定 HIV 相关 COPD 的存在和严重程度是否与肺 CD4+ T 细胞的消耗相关。在目标 3 中，我们检验了以下假设：肺 CD4+ 耗竭和失调是由于 HIV 感染和复制所致。在目标 4 中，我们检查了 HIV 相关 COPD 中肺 CD8+ T 细胞免疫激活是否增加，这至少部分是由于 CD4+ T 细胞调节机制的丧失。我们的多学科研究团队提供艾滋病毒、肺部疾病和免疫学方面的临床和研究专业知识，并在艾滋病毒和慢性阻塞性肺病方面拥有富有成效的合作记录。 SHIELD 提供了理想的研究人群和研究基础设施来进行这些临床和机制研究。总之，该提案直接解决了我们对 HIV 相关慢性阻塞性肺病的临床谱和后果的理解中的关键差距，并将确定导致该疾病的关键生物学机制。研究结果将为针对艾滋病毒相关慢性阻塞性肺病的临床管理和干预措施的制定提供信息，也可能为非艾滋病毒感染人群中更广泛的慢性阻塞性肺病策略提供信息。