HAART-mediated Immune Restoration in Chronic Obstructive Pulmonary Disease

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）与慢性疾病的风险增加有关，从心血管并发症到自身免疫性疾病。我们最近发现HAART的使用与更严重的气道阻塞独立相关。该项目的总体目标是研究通过HAART进行的免疫恢复通过对肺部病原体和/或自身抗原的慢性炎症反应的传播导致气道阻塞/慢性阻塞性肺疾病增加的假设。我们将通过对匹兹堡大学艾滋病门诊患者的前瞻性纵向研究，以及对作为多中心艾滋病队列研究和妇女机构间研究一部分的标本进行分析，来研究HAART启动的效果。研究目的：(1)验证HAART启动与气道阻塞和/或肺气肿增加相关的假设。(2)为了验证启动HAART诱导“修饰免疫恢复综合征”的假设，通过对潜在病原体的反应和/或通过揭露自身抗原来创造促炎环境。(3)验证肺囊虫或自身抗原引起的慢性炎症反应与气道阻塞和/或肺气肿增加有关的假设。本研究计划提出了一个全面的计划，通过该计划，P.I.将有助于确定HAART和COPD之间的病理生理机制，并将实现以下目标：通过进行前瞻性纵向研究的经验，拓宽候选人进行临床/转化研究的能力；2. 提高候选人在统计分析和建模方面的分析技巧；和3。通过密集的教学、会议和研究经验，将候选人转变为hiv相关肺部疾病的主要独立研究者。！

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has been linked to increased risk of chronic medical conditions, from cardiovascular complications to autoimmune diseases. We have recently found that use of HAART is independently associated with worse airway obstruction. The overall goal of this project is to investigate the hypothesis that immune restoration through HAART leads to increased airway obstruction/chronic obstructive pulmonary disease via propagation of a chronic inflammatory response to pulmonary pathogens and/or autoantigens. We will study the effects of HAART initiation through a prospective longitudinal study of HIV outpatients at the University of Pittsburgh, as well as through an analysis of specimens archived as part of the Multicenter AIDS Cohort Study and the Women's Interagency Study. Research Aims: (1) To test the hypothesis that HAART initiation is associated with increased airway obstruction and/or emphysema. (2) To test the hypothesis that initiating HAART induces a "modified immune restoration syndrome," creating a pro-inflammatory environment in response to an underlying pathogen and/or through unmasking of autoantigens. (3) To test the hypothesis that development of a chronic inflammatory response, either in response to Pneumocystis or autoantigens, is associated with increased airway obstruction and/or emphysema. Career Goals: This research proposal presents a comprehensive plan by which the P.I. will help determine pathophysiologic mechanisms connecting HAART and COPD and will also achieve the following: 1. Broaden the candidate's ability to perform clinical/translational studies through the experience of conducting a prospective longitudinal study; 2. Increase the candidate's analytical techniques in statistical analysis and modeling; and 3. Transform the candidate into a leading independent investigator in HIV-associated pulmonary disease through intensive didactics, conferences, and research experience. ! PUBLIC HEALTH RELEVANCE: This proposal represents a major step in determining the impact of HAART and immune restoration on the development of COPD and will provide a crucial foundation for future studies of HIV-related chronic lung disease. Given the increasing numbers of aging HIV-infected subjects with prolonged exposure to HIV and HAART, this study will provide important information for care and treatment of these patients.