title: Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy.
abstract: BACKGROUND
  Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART).
  
  
  METHODS
  Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients.
  
  
  RESULTS
  Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART.
  
  
  CONCLUSIONS
  Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.
authors.affiliation: Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Chang
authors.forename: Andrew
authors.initials: A
authors.lastname: Lim
authors.forename: Saleha
authors.initials: S
authors.lastname: Omarjee
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Levitz
authors.forename: Bernadett I
authors.initials: BI
authors.lastname: Gosnell
authors.forename: Tim
authors.initials: T
authors.lastname: Spelman
authors.forename: Julian H
authors.initials: JH
authors.lastname: Elliott
authors.forename: William H
authors.initials: WH
authors.lastname: Carr
authors.forename: Mohamed-Yunus S
authors.initials: MY
authors.lastname: Moosa
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000276:immunology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000097:blood / Q000276:immunology; D003454:Cryptococcus; D005656:Fungal Proteins / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D016919:Meningitis, Cryptococcal / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011994:Recombinant Proteins; D012307:Risk Factors; D013019:South Africa
chemical_list: D044966:Anti-Retroviral Agents; D000935:Antifungal Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D005656:Fungal Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; C025363:mannoproteins; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: antigen-specific T cells; cryptococcal mannoprotein; cryptococcal meningitis; cryptococcosis-associated immune reconstitution inflammatory syndrome; interferon-gamma; whole blood assay