HIV-related Accelerated Aging of the Airway Epithelium

描述(申请人提供)：随着高效抗逆转录病毒疗法的发展和广泛使用，艾滋病毒-1感染者的存活率显著提高。然而，随着存活率的提高，人们认识到艾滋病毒感染与通常与衰老有关的慢性疾病的加速发展有关。其中最常见的是慢性阻塞性肺疾病(COPD)，主要发生在吸烟者中，艾滋病毒感染和吸烟共同加速了COPD的发病和风险。为什么艾滋病毒感染是吸烟者慢性阻塞性肺病的重要危险因素？基于小气道是COPD气流阻塞的主要部位的认识，吸烟的首要病理表现是小气道上皮(SAE)，与COPD相关的肺气肿始于SAE周围的肺泡，吸烟导致SAE转录组的显著紊乱，以及我们的证据表明HIV+吸烟者SAE的端粒短于HIV吸烟者，我们认为吸烟者HIV感染导致的COPD的加速发展是由于SAE直接感染HIV所导致的SAE过早的生物衰老所致。和/或通过HIV感染的T细胞和/或肺泡巨噬细胞(AM)与SAE的相互作用。我们已经收集了一组HIV+受试者(n=305)和HIV对照组(HIV不吸烟者、健康吸烟者和患有COPD的吸烟者，总计n=2655)的研究队列，我们将每年评估15-20名新诊断的、未经治疗的HIV+患者。总而言之，我们拥有所有相关的方法和基础设施，可以开展3个具体目标中所阐述的拟议研究。目的1.在没有肺部疾病临床证据的HIV+吸烟者中，我们假设SAE过早老化；表现出类似于生物学紊乱的生物紊乱 患有慢性阻塞性肺病的艾滋病毒吸烟者的SAE。目的2.评估HIV+吸烟者SAE的加速生物老化是由于HIV感染的T细胞和/或AM直接或间接地与SAE相互作用所致目的3.评估一种假设，即严格控制病毒载量的HIV+吸烟者的T细胞和/或AM将不再能够介导与SAE相关的加速的生物衰老。总之，这些研究将有助于揭开HIV相关COPD发展的发病机制，有助于确定药物干预的新靶点，并增加证据表明，严格控制HIV感染可能有助于降低HIV相关COPD的发病率。

DESCRIPTION (provided by applicant): With the development and widespread use of highly active antiretroviral therapy, the survival of individuals infected with HIV-1 has dramatically improved. However, with this increased survival has come the recognition that HIV infection is associated with the accelerated development of chronic disorders usually associated with aging. Among the most common is chronic obstructive pulmonary disease (COPD), primarily in cigarette smokers, with the combination of HIV infection and smoking accelerating the onset and risk for COPD. Why is HIV infection such an important risk factor for COPD in smokers? Based on the knowledge that the small airways are the major site of airflow obstruction in COPD, the first pathologic manifestations of cigarette smoking are in the small airway epithelium (SAE), the emphysema associated with COPD starts in alveoli surrounding the SAE, smoking induces marked disordering of the transcriptome of the SAE, and our evidence that telomeres of SAE of HIV+ smokers are shorter than that of HIV- smokers, we propose that the accelerated development of COPD in smokers with HIV infection results from the premature biologic aging of the SAE, generated by the effects of direct HIV infection of the SAE, and/or through the interaction of HIV-infected T cells and/or alveolar macrophages (AM) with the SAE. We have assembled a study cohort of HIV+ subjects (n=305) and HIV- controls (HIV- nonsmokers, healthy smokers, and smokers with COPD, total n=2,655) and we will evaluate 15-20 newly diagnosed, untreated HIV+ individuals/yr. Together, we have all of the relevant methodologies and infrastructure to carry out the proposed studies articulated in 3 specific aims. Aim 1. In HIV+ smokers who have no clinical evidence of lung disease, we hypothesize that the SAE is aging prematurely; exhibiting biologic disordering that is similar to the disordered biology of the SAE of HIV smokers with COPD. Aim 2. To assess the hypothesis that the accelerated biologic aging of the SAE of the HIV+ smoker results from the interaction of HIV with the SAE directly or indirectly though HIV infected T cells and/or AM. Aim 3. To evaluate the hypothesis that the T cells and/or AMs of HIV+ smokers with tight control of viral loads will no longer be able to mediate the accelerated biologic aging associated with the SAE. Together, these studies will help unravel the pathogenesis of the HIV-associated development of COPD, help identify new targets for pharmacologic intervention and add to the evidence that tight control of HIV infection may be useful in reducing the incidence of HIV-associated COPD.