Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 207, Issue 12, Pages 1817-1828Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jit099
Keywords
HIV; cryptococcus neoformans; TB; CMV; memory T cells; flow cytometry
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Funding
- Wellcome Trust [WT081794, 088590]
- National Institutes of Health [RO1 AI025780]
- Intramural Research Program of the Vaccine Research Center, National Institutes of Allergy and Infectious Disease, National Institutes of Health
- National Institute for Health Research [CL-2012-20-001] Funding Source: researchfish
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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 1 alpha, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). 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-gamma or TNF-alpha 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/mu L; 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-gamma/TNF-alpha-predominant responses were associated with survival.
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