The Phenotype of the Cryptococcus-Specific CD4+Memory T-Cell Response Is Associated With Disease Severity and Outcome in HIV-Associated Cryptococcal Meningitis

• Published in: The Journal of infectious diseases Vol. 207; no. 12; pp. 1817 - 1828
• Main Authors: Jarvis, Joseph N., Casazza, Joseph P., Stone, Hunter H., Meintjes, Graeme, Lawn, Stephen D., Levitz, Stuart M., Harrison, Thomas S., Koup, Richard A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.06.2013
• Subjects: Adult; Antigens, Fungal - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cohort Studies; Cryptococcal meningitis; Cryptococcus - classification; Cryptococcus - immunology; Cryptococcus neoformans; Cytokines; Cytokines - cerebrospinal fluid; Cytomegalovirus; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; HIV - immunology; HIV Infections - complications; HIV Infections - immunology; HIV Infections - virology; HIV/AIDS; Humans; Infections; Infectious diseases; Interferon-gamma - cerebrospinal fluid; Interferons; Interleukins; Major and Brief Reports; Male; Medical sciences; Meningitis, Cryptococcal - complications; Meningitis, Cryptococcal - immunology; Meningitis, Cryptococcal - microbiology; Meningitis, Cryptococcal - mortality; Microbiology; Miscellaneous; Phenotype; Phenotypes; Severity of Illness Index; South Africa - epidemiology; T lymphocytes; T-Lymphocyte Subsets - immunology; Tuberculosis; Tumor Necrosis Factor-alpha - cerebrospinal fluid; Viral Load; Virology; South Africa; Virus; Infection; Nervous system diseases; Phenotype; CD4 T lymphocyte; Prognosis; Central nervous system disease; Retroviridae; Meningitis; Cellular immunity; Human immunodeficiency virus; Lentivirus; cryptococcus neoformans; flow cytometry; HIV; CMV; TB; memory T cells
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jit099

Background. Correlates of immune protection in patients with human immunodeficiency virus (HIV)-associated cryptococcal meningitis are poorly defined. A clearer understanding of these immune responses is essential to inform rational development of immunotherapies. Methods. Cryptococcal-specific peripheral CD4 + T-cell responses were measured in 44 patients with HIV-associated cryptococcal meningitis at baseline and during follow-up. Responses were assessed following ex vivo cryptococcal mannoprotein stimulation, using 13-color flow-cytometry. The relationships between cryptococcal-specific CD4 + T-cell responses, clinical parameters at presentation, and outcome were investigated. Results. Cryptococcal-specific CD4 + T-cell responses were characterized by the production of macrophage inflammatory protein 1α, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α). Conversely, minimal interleukin 4 and interleukin 17 production was detected. Patients surviving to 2 weeks had significantly different functional CD4 + T-cell responses as compared to those who died. Patients with a response predominantly consisting of IFN-γ or TNF-α production had a 2-week mortality of 0% (0/20), compared with 25% (6/24) in those without this response (P=.025). Such patients also had lower fungal burdens (10 400 vs 390 000 colony-forming units/mL; P < .001), higher cerebrospinal fluid lymphocyte counts (122 vs 8 cells/μL; P < .001), and a trend toward faster rates of clearance of infection. Conclusions. The phenotype of the peripheral CD4 + T-cell response to Cryptococcus was associated with disease severity and outcome in HIV-associated cryptococcal meningitis. IFN-γ/TNF-α—predomiant responses were associated with survival.