The Role of Immune Reconstitution Inflammatory Syndrome (IRIS) in Pulmonary Tuber

描述(由申请者提供)：这份申请概述了默多克博士的四年计划，该计划将导致默多克博士在独立的国际研究中的职业生涯，重点是艾滋病毒/艾滋病相关的肺结核病和呼吸道感染。这一提议的基础是在南非约翰内斯堡由杜克大学候选人大卫·默多克医学博士、北卡罗来纳大学传染病流行病学家Annelies Van rie博士和威特沃特斯兰德大学肺病学家查尔斯·费尔德曼博士在南非约翰内斯堡开展的一项国际合作。杜克大学艾滋病毒免疫学家肯特·温霍尔德博士将加入这项合作。这些导师将监督默多克博士在HIV感染患者免疫重建的不同阶段对结核病的肺间隔室免疫反应的研究。这项研究将建立在2005年启动的北卡罗来纳大学/WITS合作免疫重建炎症综合症(IRIS)研究项目的基础上。虹膜是一种矛盾的临床恶化，观察到艾滋病毒感染患者开始抗逆转录病毒治疗(ART)，通常在6个月内。我们约翰内斯堡IRIS研究的初步数据表明，在艾滋病毒患者中发起抗逆转录病毒治疗的最常见的IRIS病原体是结核分枝杆菌(TB)。随着最近在发展中国家采用抗逆转录病毒疗法，其他国家注意到在抗逆转录病毒疗法的头几个月中肺结核(PTB)发病率很高。ART术后肺结核的免疫发病机制在很大程度上仍不清楚。我们假设ART的启动引起了肺间室的炎症状态，并可能有助于IRIS-PTB的发展。为了验证这一假设，默多克博士将确定那些在抗逆转录病毒治疗前、抗逆转录病毒治疗后早期(3个月)和晚期(12个月)出现肺结核的艾滋病毒感染者，并比较他们的外周和肺免疫状况对结核病的反应。他还将对结核病分离株的耐药性和毒力模式进行表征，并对现有IRIS研究的存储样本进行T细胞表型鉴定。这些研究将有助于确定IRIS的免疫标记物，并表征处于IRIS免疫状态和非IRIS免疫状态的艾滋病毒个体对结核病的宿主病原体免疫共鸣。默多克博士将在南非进行这些研究，并获得杜克大学、北卡罗来纳大学和WITS的资源。这些研究的结果将有助于我们理解艾滋病毒/结核病合并感染，对处于各种免疫抑制状态的结核病的管理具有重要意义。

DESCRIPTION (provided by applicant): This application outlines a four year plan for Dr. Murdoch leading to a career in independent international research with a focus on HIV/AIDS-associated pulmonary TB and respiratory infections. The foundation for this proposal is an international collaboration in Johannesburg, South Africa between David Murdoch, MD, MPH, the candidate at Duke University, Annelies Van Rie, MD, PhD, an infectious disease epidemiologist at the University of North Carolina (UNC), and Charles Feldman, MD, PhD, a pulmonologist at the University of the Witwatersrand (WITS). Dr. Kent Weinhold, PhD, a HIV immunologist at Duke University, will join this collaboration. These mentors will supervise Dr. Murdoch in his study of the lung compartment immune response to TB during different stages of immune reconstitution in HIV-infected patients. This study will build upon the UNC/WITS collaborative immune reconstitution inflammatory syndrome (IRIS) research project initiated in 2005. IRIS is a paradoxical clinical deterioration observed in HIV-infected patients initiating antiretroviral therapy (ART), usually within 6 months. Preliminary data from our Johannesburg IRIS study indicates the most common IRIS pathogen in HIV patients initiating ART is Mycobacerium tuberculosis (TB). With the recent introduction of ART in developing countries, others have noted a high incidence of pulmonary tuberculosis (PTB) in the first months of ART. The immunopathogenesis of post-ART PTB remains largely unknown. We hypothesize ART initiation elicits an inflammatory state in the lung compartment and may contribute to the development of IRIS-PTB. To test this hypothesis, Dr. Murdoch will identify HIV-infected individuals who develop PTB pre-ART, early (<3 months) post-ART, and late (>12 months) post-ART, and compare their peripheral and lung immune profiles in response to TB. He will also characterize resistance and virulence patterns of the TB isolates and perform T cell phenotyping on stored samples from the existing IRIS study. These studies will help identify immune markers for IRIS and characterize the host-pathogen immune resonse to TB in HIV individuals, both in an IRIS and non-IRIS immune state. Dr. Murdoch will perform these studies in South Africa with access to the resources of Duke, UNC, and WITS. The results of these studies will contribute to our understanding of HIV/TB coinfection, with important implications on the management of TB in various immuosuppressive states.