Inflammation, Aging, Microbes, Obstructive Lung Disease and Diffusion Abnormalities (I AM OLD-DA) Study

摘要 慢性阻塞性肺疾病(COPD)是一种与艾滋病毒相关的肺部疾病，也是 随着全世界艾滋病毒+人群的老龄化，其发病率和死亡率及其临床意义也在增加。尽管 这一点，我们对HIV+COPD的发病机制的了解是有限的，但HIV相关和COPD- 具体的机制是假设的。提高认识对于开发新的治疗方法至关重要 治疗或预防这一日益严重的问题。这项研究建立在一个新的、成熟的跨国公司(美国和乌干达)的基础上 HIV+人群的队列。这项研究测量了免疫激活、炎症、肺损伤、 以及血液和肺标本中的细胞老化。这项研究还进行了肺功能测试和 检查了选定的标志物和肺功能之间的关系。我们的数据显示，不同的标志物 与不同的肺功能异常有关，提示这些肺功能异常可能 这是由于不同的潜在机制造成的。有趣的是，巨细胞病毒(CMV)是一种慢性病毒 在HIV+人群中常见的感染，已经与三个最密切相关的标志有关 肺功能异常之一。这些数据产生了以下具体目标：目标1和目标2：测试 假设选定的免疫激活、炎症、肺损伤和 在血液中测量的细胞老化与随后的肺功能和 与每个肺功能异常相关的特定标志物将是不同的。纵向研究 设计将加强我们早期工作的因果推论，并将为未来的试验奠定基础 治疗干预措施，包括具有潜在新颖性和/或不同的个性化医疗的潜力 针对不同生物标志物和/或不同肺功能异常的治疗。目标3.在横截面子集中 选择接受支气管镜检查并收集肺部样本的HIV+参与者，以检验以下假设 同一标志物中的异常，但现在在肺标本中测量到的异常与异常肺有关 功能，并验证无症状CMV合并感染也与肺功能相关的假设 异常并由这些标记物介导。这一目标将决定是否涉及CMV合并感染 在肺功能异常方面，并可能为HIV+COPD的抗CMV治疗试验奠定基础。至 为了实现这些目标，我们将对400名HIV+受试者进行纵向研究(200名在美国，200名在乌干达) 并在肺功能检测的同时采集和储存血液样本。我们还将表演 对80名受试者(美国40名，乌干达40名)进行支气管镜检查，并收集和储存肺标本 并在进行肺功能检测的同时对标本进行巨细胞病毒联合感染评估。保存的标本 将允许在未来对新的和新的标记进行有效的测试。我们的长期目标是改善我们的 对HIV感染者肺功能异常的机械性理解将导致未来 测试针对这一重要且日益严重的临床问题的新疗法的研究。

ABSTRACT Chronic obstructive pulmonary disease (COPD) is an HIV-associated lung disease and a leading cause of morbidity and mortality, and its clinical significance is increasing as the HIV+ population ages worldwide. Despite this, our understanding of the mechanisms underlying HIV+ COPD is limited but both HIV-related and COPD- specific mechanisms are hypothesized. An improved understanding is critical for developing new therapies to treat or prevent this growing problem. This study builds upon a novel, established multinational (US and Uganda) cohort of HIV+ persons. The study measured selected markers of immune activation, inflammation, lung injury, and cellular aging in both blood and lung specimens. The study also performed lung function testing and examined the associations between the selected markers and lung function. Our data show that different markers are associated with different lung function abnormalities, suggesting that these lung function abnormalities may be due to different underlying mechanisms. Interestingly, cytomegalovirus (CMV), which is a chronic viral infection common in HIV+ persons, has been associated with the three markers most strongly associated with one of the lung function abnormalities. These data lead to the following specific aims: Aims 1 and 2: To test the hypothesis that persistent abnormalities in selected markers of immune activation, inflammation, lung injury, and cellular aging measured in the blood are associated with subsequent changes (declines) in lung function and that the specific markers associated with each lung function abnormality will be different. The longitudinal study design will strengthen the causal inferences from our earlier work and will set the foundation for future trials of therapeutic interventions, including the potential for personalized medicine with potentially novel and/or different therapies for different biomarker and/or different lung function abnormalities. Aim 3. In a cross-sectional subset of HIV+ participants selected to undergo bronchoscopy and collect lung specimens, to test the hypothesis that abnormalities in the same markers but now measured in lung specimens are associated with abnormal lung function and test the hypothesis that asymptomatic CMV co-infection is also associated with lung function abnormalities and is mediated by these markers. This aim will determine whether CMV co-infection is involved in lung function abnormalities and potentially set the stage for trials of anti-CMV therapy in HIV+ COPD. To address these aims, we will conduct a longitudinal study of 400 HIV+ subjects (200 in the US and 200 in Uganda) and collect and bank blood specimens at the same time as lung function testing. We will also perform bronchoscopy in a subset of 80 subjects (40 in the US and 40 in Uganda) and collect and bank lung specimens and specimens to assess for CMV co-infection at the same time as lung function testing. The banked specimens will allow for efficient testing of new and novel markers in the future. Our long-term objective is to improve our mechanistic understanding of lung function abnormalities seen in persons with HIV that would lead to a future study that tests new treatments for this important and growing clinical problem.