title: The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis.
abstract: 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-predominant responses were associated with survival.
authors.affiliation: Research Centre for Infection and Immunity, Division of Clinical Sciences, St. George's University of London, UK.joejarvis@doctors.net.uk
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Jarvis
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.forename: Hunter H
authors.initials: HH
authors.lastname: Stone
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lawn
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Levitz
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Harrison
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000328:Adult; D000946:Antigens, Fungal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D003454:Cryptococcus / Q000145:classification / Q000276:immunology*; D016207:Cytokines / Q000134:cerebrospinal fluid; D005260:Female; D005500:Follow-Up Studies; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000134:cerebrospinal fluid; D008297:Male; D016919:Meningitis, Cryptococcal / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D010641:Phenotype; D012720:Severity of Illness Index; D013019:South Africa / Q000453:epidemiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid; D019562:Viral Load
chemical_list: D000946:Antigens, Fungal; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: CMV; HIV; TB; cryptococcus neoformans; flow cytometry; memory T cells