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

描述（由申请人提供）：本申请概述了默多克博士的四年计划，该计划将致力于独立的国际研究，重点是艾滋病毒/艾滋病相关的肺结核和呼吸道感染。该提案的基础是大卫默多克，医学博士，公共卫生硕士，杜克大学的候选人，Annelies货车Rie，医学博士，哲学博士，北卡罗来纳州大学的传染病流行病学家，以及威特沃特斯兰德大学（WITS）的肺病学家Charles Feldman，医学博士，哲学博士在南非约翰内斯堡的国际合作。杜克大学的艾滋病免疫学家肯特温霍尔德博士将加入这一合作。这些导师将监督默多克博士在他的研究肺室免疫反应结核在不同阶段的免疫重建艾滋病毒感染的患者。这项研究将建立在2005年启动的WITS/WITS合作免疫重建炎症综合征（IRIS）研究项目的基础上。IRIS是在开始抗逆转录病毒治疗（ART）的HIV感染患者中观察到的一种矛盾的临床恶化，通常在6个月内。来自我们约翰内斯堡IRIS研究的初步数据表明，在开始ART的HIV患者中，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引入ART，其他人已经注意到在ART的头几个月肺结核（PTB）的发病率很高。ART后PTB的免疫发病机制在很大程度上仍然未知。我们假设ART启动会引发肺室的炎症状态，并可能有助于IRIS-PTB的发展。为了验证这一假设，Murdoch博士将确定ART前、ART后早期（<3个月）和ART后晚期（>12个月）发生PTB的HIV感染者，并比较他们对TB的外周和肺部免疫特征。他还将描述结核病分离株的耐药性和毒力模式，并对现有IRIS研究的储存样本进行T细胞表型分析。这些研究将有助于确定IRIS的免疫标记物，并描述HIV个体中对结核病的宿主-病原体免疫应答，无论是在IRIS还是非IRIS免疫状态下。Murdoch博士将在南非进行这些研究，并可使用杜克大学、麻省理工学院和WITS的资源。这些研究的结果将有助于我们了解艾滋病毒/结核病合并感染，具有重要意义的管理结核病在各种免疫抑制状态。

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.