Cryptococcosis-IRIS is Associated With Lower Cryptococcus-specific IFN-γ Responses Before Antiretroviral Therapy but Not Higher T-Cell Responses During Therapy

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-gamma), 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-gamma, 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. Conclusion. 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-gamma production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.