Longitudinal evaluation of HIV-associated lung disease phenotypes

HIV 相关肺部疾病表型的纵向评估

• 批准号: 8913261
• 负责人: John W Mellors
• 金额: $ 72.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913261
• 关键词: Address; Adverse effects; Age; Biological Markers; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; C-reactive protein; CD14 Antigen; CD14 gene; CD4 Lymphocyte Count; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Comorbidity; Cytomegalovirus; DNA; Data; Deterioration; Development; Diffuse; Disease; Dyspnea; Early Diagnosis; Endothelin-1; Evaluation; Functional disorder; Future; Goals; HIV; HIV Infections; Hepatitis C; Human immunodeficiency virus test; IL8 gene; Image; Immunologic Deficiency Syndromes; Impairment; Individual; Infection; Interleukin-6; Intervention; Knowledge; Link; Lung; Lung diseases; Measures; Methods; Morbidity - disease rate; Obstruction; Organ; Outcome; Outpatients; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Physiological; Plasma; Play; Population; Procedures; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Hypertension; RNA; Research Proposals; Residual state; Resources; Respiratory physiology; Risk; Risk Factors; Role; Sampling; Smoker; Smoking; Source; Specimen; Subgroup; Symptoms; Testing; Therapeutic Intervention; United States; Vascular Endothelium; Vasoconstrictor Agents; Viral; Virus; Virus Diseases; Work; airway obstruction; antiretroviral therapy; co-infection; cohort; disease phenotype; disorder prevention; disorder risk; follow-up; high risk; immune activation; improved; innovation; insight; interest; lung development; macrophage; microbial; mortality; never smoker; novel; personalized medicine; prevent; public health relevance; pulmonary function; receptor; repository; respiratory; response; screening; targeted treatment; tool; treatment trial

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.

描述（由申请人提供）：项目摘要/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疗法（ART）时代，COPD也在艾滋病毒中加速。由于尚未在HIV中开发或测试过标准的COPD治疗，因此它们可能缺乏疗效或具有重大副作用。了解COPD在艾滋病毒中的发展方式对于识别预防疾病和治疗的新目标很重要。我们已经表明，艾滋病毒中COPD的不同但经常重叠的表型存在，并且在理解COPD发病机理和个性化治疗方面至关重要。我们的工作表明，> 70％的HIV+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有关，死亡率与吸烟和CD4细胞计数无关。该提案的目标是利用我们现有的纵向队列，生物特异性和成像库来解决科学差距，以理解表型和HIV肺疾病的发病机理，并将HIV+队列的随访扩展到10年。该提案的总体假设是HIV COPD的离散表型在其轨迹，生物标志物和危险因素上有所不同，并且包括持续性病毒感染或微生物易位在内的共同感染与HIV COPD相关联。结果将是迄今为止在艺术时代对肺功能的最长研究，它将使我们能够发展出更好的疾病风险标记，识别机械途径，并针对高风险个体以进行未来的干预措施。我们将以以下目的来检验我们的假设1。用于检验HIV COPD表型具有多种疾病轨迹和对ART的可变反应的假设。目的2。为了检验HIV COPD表型具有独特的生物标志物的假设，并且特定的生物标志物鉴定出危险人群。目的3。为了检验以下假设：HIV持久性，病毒共感染或微生物易位与异常肺功能有关。该研究建议专门解决了HIV COPD中的几个关键知识差距，这是非辅助发病率和死亡率的重要原因。鉴于多年来发现COPD的变化，因此有必要使用纵向，良好的人群来评估这些重要且不断发展的并发症。我们将利用我们已建立的多中心队列来确定10年内HIV COPD表型的进程，并回答有关HIV COPD的几个关键问题，包括艺术启动的影响，外围生物标志物的效用以及残留HIV的作用，以及其他慢性抗原刺激的其他来源在肺功能障碍中。这项创新的建议将利用现有资源，并很可能会提高人们对艾滋病毒疾病的了解，确定新型的生物标志物和治疗靶标，并填补有关慢性感染在HIV相关COPD中作用的知识的空白，这是对RFA-14-023的目的直接响应。