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

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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.