Longitudinal evaluation of HIV-associated lung disease phenotypes

描述（由申请人提供）：项目概述/摘要慢性阻塞性肺疾病（COPD）的特征是气道阻塞和呼吸困难，是美国第四大死亡原因。即使在当前的抗逆转录病毒治疗（ART）时代，COPD在HIV中也会加速。由于标准的COPD治疗方法尚未开发或测试艾滋病毒，它们可能缺乏疗效或具有显著的副作用。了解COPD如何在HIV中发展对于确定疾病预防和治疗的新靶点非常重要。我们已经表明，不同的，但往往重叠的COPD表型存在于艾滋病毒，并在了解COPD发病机制和个性化治疗的关键。我们的工作表明，>70%的HIV+门诊患者表现出至少一种COPD表型。这些表型与呼吸道症状的更大负担以及与独立于吸烟和CD 4细胞计数的死亡率相关。该提案的目标是利用我们现有的纵向队列、生物标本和成像库，以解决在理解HIV肺部疾病的表型和发病机制方面的科学差距，并将我们的HIV+队列的随访时间延长至10年。该提案的总体假设是HIV COPD的离散表型在其轨迹、生物标志物和风险因素方面不同，并且包括持续病毒感染或微生物易位在内的合并感染与HIV COPD相关。结果将是ART时代迄今为止最长的肺功能研究，并将使我们能够开发更好的疾病风险标志物，确定机制途径，并针对高风险个体进行未来干预。我们将测试我们的假设与以下目标目标1.检验HIV COPD表型具有不同的疾病轨迹和对ART的可变反应的假设。目的2。检验HIV COPD表型具有独特生物标志物以及特定生物标志物可识别高危个体的假设。目标3。检验HIV持续存在、病毒合并感染或微生物易位引起的慢性抗原刺激与肺功能异常相关的假设。这项研究计划专门针对艾滋病毒慢性阻塞性肺病，非艾滋病发病率和死亡率的重要原因几个关键的知识差距。鉴于COPD的变化是多年来观察到的，因此有必要使用纵向的、特征良好的队列来评价这些重要的和不断发展的并发症。我们将利用我们已建立的多中心队列，确定10年内HIV COPD表型的病程，并回答有关HIV COPD的几个关键问题，包括ART启动的影响，外周生物标志物的效用，以及残留HIV（肺功能障碍中慢性抗原刺激的其他来源）的作用。这项创新提案将利用现有资源，极有可能促进对HIV肺病的理解，确定新的生物标志物和治疗靶点，并填补有关慢性感染在HIV相关COPD中作用的知识空白，这是RFA-14-023的直接响应目标。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction and dyspnea and is the fourth leading cause of death in the United States. COPD is accelerated in HIV even in the current era of antiretroviral therapy (ART). Because standard COPD treatments have not been developed for or tested in HIV, they may lack efficacy or have significant side effects. Understanding how COPD develops in HIV is important in identifying novel targets for disease prevention and treatment. We have shown that distinct, but often overlapping phenotypes of COPD exist in HIV and are critical in understanding COPD pathogenesis and in personalizing treatment. Our work indicates that >70% of HIV+ outpatients manifest at least one COPD phenotype. These phenotypes are associated with a greater burden of respiratory symptoms and with mortality independent of smoking and CD4 cell count. Goals of this proposal are to utilize our existing longitudinal cohort, bio-specimens, and imaging bank to address scientific gaps in understanding of phenotypes and pathogenesis of HIV pulmonary disease and to extend follow-up of our HIV+ cohort up to 10 years. The overall hypotheses of this proposal are that discrete phenotypes of HIV COPD differ in their trajectories, biomarkers, and risk factors and that co-infections including persistent viral infection or microbial translocation are linked t HIV COPD. Results will be the longest study of lung function to date in the era of ART and will allow us to develop better markers of disease risk, identify mechanistic pathways, and target high-risk individuals for future interventions. We will test our hypotheses with the following aims Aim 1. To test the hypothesis that HIV COPD phenotypes have diverse disease trajectories and variable response to ART. Aim 2. To test the hypothesis that HIV COPD phenotypes have unique biomarkers and that specific biomarkers identify at-risk individuals. Aim 3. To test the hypothesis that chronic antigenic stimulation from HIV persistence, viral co-infections, or microbial translocation is linked to abnormal lung function. This research proposal specifically addresses several critical knowledge gaps in HIV COPD, an important cause of non-AIDS morbidity and mortality. Given that changes in COPD are seen over many years, it is necessary that longitudinal, well-characterized cohorts are used to evaluate these important and evolving complications. We will utilize our established, multicenter cohort to determine the course of HIV COPD phenotypes over 10 years and answer several key questions about HIV COPD including the effect of ART initiation, the utility of peripheral biomarkers, and the role of residual HIV an other sources of chronic antigenic stimulation in lung dysfunction. This innovative proposal will leverage existing resources and is highly likely to advance understanding of HIV lung disease, identify novel biomarkers and targets for therapy, and fill gaps in knowledge about the role of chronic infections in HIV-associated COPD, an objective directly responsive to RFA-14-023.