HIV Immune Reconstitution Inflammatory Syndrome (IRIS) is a newly recognized complication of anti- retroviral therapy (ART) whereby some persons initiating ART experience paradoxically clinical deterioration due to an exaggerated inflammatory response to occult, latent, or previously treated infections. HIV IRIS has emerged as a frequent complication of ART in Sub-Saharan Africa. As cryptococcal meningitis (CM) is the second most common AIDS-defining illness in sub-Saharan Africa, CM-IRIS is a common problem. CM-IRIS is an ideal disease model for studying the epidemiology and pathogenesis of IRIS because CM IRIS causes a distinct, easily recognized clinical syndrome characterized by a clear phenotype of aseptic meningitis. The characteristics of CM-IRIS can be studied at the site of inflammation by sampling cerebrospinal fluid (CSF) from, the compartment where the inflammation occurs. This project is a prospective cohort study of HIV-infected Ugandans with recent CM monitored on ART. The candidate will determine if persons who develop IRIS have worse outcomes compared to persons who do not develop IRIS in a resource-limited area. The candidate will determine if HIV-infected Ugandan patients who develop CM IRIS express biomarkers in their peripheral blood and CSF that can be used to diagnose IRIS or predict which patients are at risk of IRIS. Dr. Boulware's long term career goal is to become an independent translational researcher who bridges the gap between basic science and clinical research, moving basic science concepts to clinical application. This award will provide for mentored development of laboratory research skills in immunology and functional genomics with application of these skills in an international setting.

Public Health Relevance

In Sub-Saharan Africa, cryptococcal meningitis is the second most common AIDS-defining illness, and causes -30% of the AIDS-related attributable mortality. For those surviving their cryptococcal infection who now have access to ART, IRIS occurs in approximately one in three persons and is frequently fatal (40-66%) in resource-limited regions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
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Bacon, Melanie C
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Boulware, David R; von Hohenberg, Maximilian; Rolfes, Melissa A et al. (2016) Human Immune Response Varies by the Degree of Relative Cryptococcal Antigen Shedding. Open Forum Infect Dis 3:ofv194
Rajasingham, Radha; Rhein, Joshua; Klammer, Kate et al. (2015) Epidemiology of meningitis in an HIV-infected Ugandan cohort. Am J Trop Med Hyg 92:274-9
Scriven, James E; Rhein, Joshua; Hullsiek, Katherine Huppler et al. (2015) Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial. J Infect Dis 212:769-78
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Rolfes, Melissa A; Rhein, Joshua; Schutz, Charlotte et al. (2015) Cerebrospinal Fluid Culture Positivity and Clinical Outcomes After Amphotericin-Based Induction Therapy for Cryptococcal Meningitis. Open Forum Infect Dis 2:ofv157
Boulware, David R; Rolfes, Melissa A; Rajasingham, Radha et al. (2014) Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis 20:45-53
Bahr, Nathan C; Wallace, James; Frosch, Anne E P et al. (2014) Unmasking Cryptococcal Meningitis Immune Reconstitution Inflammatory Syndrome due to Granulocyte Colony-Stimulating Factor Use in a Patient with a Poorly Differentiated Germ Cell Neoplasm. Case Rep Oncol 7:1-5
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Carlson, Renee Donahue; Rolfes, Melissa A; Birkenkamp, Kate E et al. (2014) Predictors of neurocognitive outcomes on antiretroviral therapy after cryptococcal meningitis: a prospective cohort study. Metab Brain Dis 29:269-79

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