HIV and COPD:Immune mediated mechanisms

描述（由申请人提供）：全球有超过3000万人感染艾滋病毒。在慢性艾滋病毒感染者中，肺病是发病率和死亡率的主要原因。艾滋病毒感染增加了慢性阻塞性肺疾病（COPD）以及其他肺部疾病的发病率。事实上，在一些研究中，艾滋病毒感染者的呼吸道症状和/或肺功能检查异常（pft）的发生率高达60%。HIV引起非传染性肺部疾病的机制尚不清楚。有人认为，艾滋病病毒引起的免疫失调是这一过程的重要因素。此外，病毒对肺细胞的直接作用、氧化应激、慢性低级别肺部感染和抗逆转录病毒治疗（ART）的使用可能有助于这些疾病的发病机制。对hiv相关肺部疾病分子机制的进一步了解可能有助于识别新的生物标志物，促进预防方法，并指导新疗法的开发。然而，确定慢性HIV感染的COPD确切发病机制的研究仍然有限。为了更好地确定慢性HIV中COPD的分子机制，我们建议使用先进的成像技术、支气管镜检查和先进的免疫检测对HIV感染受试者进行广泛的表型分析，并将这些措施与COPD的发病率和进展联系起来。我们假设在慢性HIV感染患者中，小气道和肺血管的反复损伤导致肺气肿改变和肺血管重塑，从而导致COPD。使用一组慢性HIV感染患者，我们将识别有气道阻塞的受试者，并将其与肺功能正常的受试者进行比较。我们将进一步使用高分辨率计算机断层扫描（HRCT），超声心动图和正电子发射断层扫描（PET）与13n2 -盐水进行表型分析。这些成像技术将提供定量的解剖和生理数据，包括对肺和肺血管破坏、局部肺通气和局部肺灌注的极其敏感的测量。这些数据将与支气管肺泡灌洗液和外周血中T细胞活性和氧化应激的评估相关。此外，我们将通过代谢组学和基因表达研究广泛探索该人群中COPD的其他潜在原因。我们还将利用一组独特的精英HIV控制者来探索ART在COPD发病机制中的潜在作用。具体目的是：1)确定慢性HIV患者T细胞慢性活化、肺损伤和COPD之间的关系；2)检测慢性HIV患者肺部氧化应激水平，明确其对肺损伤和COPD的贡献。

DESCRIPTION (provided by applicant): More than 30 million people worldwide are living with HIV. In individuals with chronic HIV infection, lung disease is a major cause of morbidity and mortality. HIV infection increases the incidence of chronic obstructive pulmonary disease (COPD), as well as other lung diseases. In fact, the incidence of respiratory symptoms and/or abnormal pulmonary function tests (PFTs) in people with HIV is as high as 60% in some studies. The mechanisms causing non-infectious pulmonary disease in HIV are poorly understood. It has been suggested that immune dysregulation from HIV is an important contributor to the process. In addition, direct effects of the virus on lung cells, oxidative stres, chronic low-grade infection of the lung, and antiretroviral therapy (ART) use may contribute to the pathogenesis of these disorders. An increased understanding of the molecular mechanisms involved in HIV-associated lung disease may help identify novel biomarkers, facilitate preventative approaches, and guide the development of novel therapies. However, studies to determine the exact pathogenesis of COPD in chronic HIV infection have been limited. To better define the molecular mechanisms of COPD in chronic HIV, we propose to extensively phenotype HIV infected subjects using cutting-edge imaging technologies, bronchoscopy, and advanced immune assays, and correlate these measures to the incidence and progression of COPD. We hypothesize that in patients with chronic HIV infection, repeated injury to the small airways and the pulmonary vasculature result in emphysematous changes and pulmonary vascular remodeling leading to COPD. Using a cohort of patients with chronic HIV infection, we will identify subjects with airway obstruction and compare them to subjects with normal lung function. We will further phenotype subjects using high resolution computed tomography (HRCT), echocardiography, and positron emission tomography (PET) with 13N2-saline. These imaging techniques will provide quantitative anatomic and physiologic data, including extremely sensitive measurements of lung and pulmonary vascular destruction, regional lung ventilation, and regional lung perfusion. These data will be correlated with assessment of T cell activity and oxidative stress in bronchoalveolar lavage (BAL) fluid and peripheral blood. In addition, we will broadly explore other potential causes for COPD in this population with metabolomic, and gene expression studies. We will also explore the potential role of ART in COPD pathogenesis by utilizing a unique cohort of elite HIV controllers. The specific aims are: 1) To determine the relationship between chronic activation of T cells, lung injury and COPD in chronic HIV; 2) To determine levels of oxidative stress in the lung of patients with chronic HIV and define the contribution to lung injury and COPD.