A third of adults with AIDS and cryptococcal meningitis (CM) develop immune reconstitution inflammatory syndrome (IRIS) after initiating antiretroviral therapy (ART), which is thought to result from exaggerated inflammatory antigen-specific T cell responses. The contribution of monocytes to the immunopathogenesis of cryptococcal IRIS remains unclear. We compared monocyte subset frequencies and immune responses in HIV-infected Ugandans at time of CM diagnosis (IRIS-Baseline) for those who later developed CM-IRIS, controls who did not develop CM-IRIS (Control-Baseline) at CM-IRIS (IRIS-Event), and for controls at a time point matched for ART duration (Control-Event) to understand the association of monocyte distribution and immune responses with cryptococcal IRIS. At baseline, stimulation with IFN-γ ex vivo induced a higher frequency of TNF-α-and IL-6-producing monocytes among those who later developed IRIS. Among participants who developed IRIS, ex vivo IFN-γ stimulation induced higher frequencies of activated monocytes, IL-6+, TNF-α+ classical, and IL-6+ intermediate monocytes compared with controls. In conclusion, we have demonstrated that monocyte subset phenotype and cytokine responses prior to ART are associated with and may be predictive of CM-IRIS. Larger studies to further delineate innate immunological responses and the efficacy of immunomodulatory therapies during cryptococcal IRIS are warranted.
Bibliographical noteFunding Information:
We thank Abdu Musubire, Nabeta Henry, Joshua Rhein, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Radha Rajasingham, Catherine Nanteza, Richard Kwizera, and Darlisha Williams for patient care. We thank Tihana Bicanic, Lewis Haddow, and Jason Baker for generously serving on the external IRIS adjudication committee. We also thank the institutional support from the Infectious Diseases Institute, specifically Alex Coutinho and Keith McAdam. We also thank Britta Flach and Alison Taylor from Makerere University Walter Reed Project and Harsh Pratap (University of Colorado Denver, Denver Veterans Affairs Medical Center) for excellent laboratory support. This work was supported by the National Institutes of Health (R01AI078934, U01AI089244, R21NS065713, R01AI108479, K24AI096925, T32AI055433-MDB, DRB, BPR); the Welcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM), the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service-(JEN). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research (WSM). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Cryptococcal meningitis
- Innate immune response