Longitudinal evaluation of HIV-associated lung disease phenotypes

慢性阻塞性肺疾病（COPD）以气道阻塞和呼吸困难为特征，是美国第四大死亡原因。即使在目前抗逆转录病毒治疗（ART）的时代，艾滋病毒也会加速COPD的发展。由于标准的慢性阻塞性肺病治疗方法尚未针对艾滋病毒开发或测试，因此它们可能缺乏疗效或有明显的副作用。了解慢性阻塞性肺病如何在HIV中发展对于确定疾病预防和治疗的新靶点非常重要。我们已经证明，HIV中存在不同但经常重叠的COPD表型，这对于理解COPD发病机制和个性化治疗至关重要。我们的研究表明，约70%的HIV阳性门诊患者至少表现出一种COPD表型。这些表型与更大的呼吸道症状负担以及与吸烟和CD4细胞计数无关的死亡率有关。本提案的目标是利用我们现有的纵向队列、生物标本和影像库来解决在理解HIV肺部疾病的表型和发病机制方面的科学空白，并将我们的HIV+队列的随访时间延长至10年。该建议的总体假设是，HIV慢性阻塞性肺病的离散表型在其轨迹、生物标志物和危险因素方面存在差异，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慢性阻塞性肺病有关。结果将是迄今为止ART时代最长的肺功能研究，并将使我们能够开发更好的疾病风险标记物，确定机制途径，并针对未来干预的高风险个体。我们将用以下目标来检验我们的假设。验证HIV COPD表型具有不同的疾病轨迹和对ART的不同反应的假设。目标2。为了验证HIV COPD表型具有独特的生物标志物和特定生物标志物识别高危个体的假设。目标3。为了验证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有关的假设。这项研究计划特别解决了艾滋病慢性阻塞性肺病的几个关键知识空白，这是非艾滋病发病率和死亡率的重要原因。鉴于COPD的变化可以观察多年，有必要采用纵向的、特征明确的队列来评估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来确定HIV - COPD表型在10年内的病程，并回答关于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、残留HIV和其他慢性抗原刺激来源在肺功能障碍中的作用。这一创新建议将利用现有资源，极有可能促进对HIV肺部疾病的理解，确定新的生物标志物和治疗靶点，并填补慢性感染在HIV相关COPD中的作用的知识空白，这是一个直接响应RFA-14-023的目标。

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.