HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses

Abstract

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.

Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co‐infection

“…Moreover, aberrant immune activation and exuberant inflammation are associated with poor disease outcome in HIV‐associated Cryptococcus neoformans meningitis infection in Uganda 32,50 . Interestingly, the evoked cytokine response to Cryptococcus GXM can be manipulated in experimental setting 96,97 . But, to our knowledge, whether evoked immune response is different with infecting Cryptococcus species is not very clear.…”

“…32,50 Interestingly, the evoked cytokine response to Cryptococcus GXM can be manipulated in experimental setting. 96,97 But, to our knowledge, whether evoked immune response is different with infecting Cryptococcus species is not very clear. Moreover, unlike C neoformans sensu lato that causes disseminated infection, C gattii sensu lato establishes localised infection.…”

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

“…Curiously, this appears associated with an aquaporin critical for brain water flow regulation that depends on Th1 [ 122 ]. In another report, Meya et al showed that aberrant T-cell function leads to subsequent increases in cytokine responses, with a lower frequency of memory subsets of CD4 and CD8 T-cells expressing IL-2, IL-17 and IFN-γ [ 123 ]. While others have found that early ART introduction was associated with decreases in non-cryptococcal IRIS incidence, Boulware et al recently showed that deferring ART for five weeks improves survival in PLWH presenting with cryptococcal meningitis, primarily in those with lower white cell counts in the cerebrospinal fluid [ 124 ].…”

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches

“…Excessive expression of chemokines and integrins in peripheral blood precedes CM-IRIS and can be assessed by monitoring patients during pathological immune reconstitution [ 31 ]. Plasma levels of cytokines, such as IL-6, IL-18, TNF-α, IL-5, IL-7, IL-17, GM-CSF, CCL11, and CXCL10, are increased in patients who develop CM-IRIS [ 84 , 85 , 86 ]. These cytokines represent mediators of a systemic immune response and local inflammatory events that occur in the central nervous system (CNS) [ 86 ].…”

“…Poor antibody response to cryptococcal antigens indicates the important role of antibody-mediated cryptococcal antigen clearance. A longitudinal study using blood leucocytes from patients with HIV and CM (with and without IRIS) showed disproportionate cellular expansion of CD66+CD16+/− neutrophils and deactivated monocyte subpopulations, but no increases in T-helper cell type 1 populations after antifungal treatment, which conferred the inability to clear Cryptococcal antigens [ 84 , 88 ]. Peripheral blood from patients who had fatal outcomes revealed low GXM- and LPS-driven monocyte responses (CD16+/−HLA-DR low ) and reduced TNF-α, but increased IL-6, IL-10, and CXCL10 production [ 88 ].…”