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: 9086463
• 负责人: John W Mellors
• 金额: $ 6.33万
• 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/9086463
• 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/摘要慢性阻塞性肺病（COPD）的特点是气道阻塞和呼吸困难，是美国第四大死因。即使在当前的抗逆转录病毒治疗（ART）时代，慢性阻塞性肺病（COPD）在艾滋病毒中也会加速。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具有显着的副作用。了解慢性阻塞性肺病在艾滋病毒中如何发展对于确定疾病预防和治疗的新目标非常重要。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。这些表型与更大的呼吸道症状负担以及独立于吸烟和 CD4 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、生物样本和成像库来解决对 HIV 肺部疾病表型和发病机制理解方面的科学差距，并将 HIV+ 队列的随访时间延长至 10 年。该提案的总体假设是，HIV COPD 的不同表型在其轨迹、生物标志物和危险因素方面有所不同，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，将使我们能够开发更好的疾病风险标记，确定机制途径，并针对高风险个体进行未来干预。我们将通过以下目标来检验我们的假设 目标 1. 检验 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. 检验以下假设：HIV COPD 表型具有独特的生物标志物，并且特定的生物标志物可识别高危个体。目标 3. 检验以下假设：HIV 持续存在、病毒合并感染或微生物易位导致的慢性抗原刺激与肺功能异常有关。这项研究提案专门解决了艾滋病毒慢性阻塞性肺病（非艾滋病发病率和死亡率的一个重要原因）的几个关键知识差距。鉴于慢性阻塞性肺病的变化多年来一直存在，因此有必要使用纵向、特征明确的队列来评估这些重要且不断变化的并发症。我们将利用我们已建立的多中心队列来确定 10 年来 HIV COPD 表型的病程，并回答有关 HIV COPD 的几个关键问题，包括 ART 启动的效果、外周生物标志物的效用以及残留 HIV 和其他来源的作用。肺功能障碍的慢性抗原刺激。这项创新提案将利用现有资源，极有可能促进对 HIV 肺部疾病的了解，确定新的生物标志物和治疗靶点，并填补关于慢性感染在 HIV 相关 COPD 中的作用的知识空白，这是 RFA 直接响应的目标-14-023。