Background. Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood. Methods. We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). Results. At diagnosis, highly activated CD8+ T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4+ T cells (increased from 2.2% to 23%; P =. 06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P =. 03). CSF cellular responses were distinct from responses in peripheral blood. Conclusions. After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4+ T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS.
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Acknowledgments. We thank Abdu Musubire, MMed; Nabeta Henry, MBChB; Joshua Rhein, MD; Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Catherine Nanteza, Richard Kwizera, MSc; and Darlisha Williams, MPH 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 Disease Institute, specifically Alex Coutinho and Keith McAdam. We also thank Britta Flach and Alison Taylor (Makerere University Walter Reed Project) and Harsh Pratap (University of Colorado, Denver Veterans Affairs Medical Center) for laboratory support.
Financial support. This work was supported by the National Institutes of Health (grants R01AI078934, U01AI089244, NS065713, R01AI108479, K24AI096925, T32AI055433, and R21NS065713); the Wellcome Trust (Training Health Researchers into Vocational Excellence [THRiVE]) in East Africa (grant 087540), the GlaxoSmithKline Collaborative Investigator Research Award, and the Veterans Affairs Research Service.
- Cell activation
- Cerebrospinal fluid
- Cryptococcal meningitis
- Immune responses