Cryptococcal meningitis remains a significant
opportunistic infection among HIV-infected patients, contributing 15-20% of HIV-related mortality. A complication of initiating antiretroviral
therapy (ART) following
opportunistic infection is
immune reconstitution inflammatory syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with
cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and
cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At
meningitis diagnosis, stimulation with cryptococcal
capsule component,
glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular
cytokines (IL-2, IFN-γ, and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust
IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell
cytokine production in response to cryptococcal
antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM
infection.