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Systemic levels of interleukin (IL)-7 at antiretroviral therapy (ART) initiation have previously been shown to be predictive of HIV-linked paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We therefore explored IL-7/IL-7 receptor (IL-7/IL-7R) signaling pathway dysfunction, with related alterations in immune function, as a mechanism underlying C-IRIS.HIV-infected patients with cryptococcal meningitis (CM) who experienced C-IRIS (n=27) were compared to CD4+ T-cell count-matched counterparts without C-IRIS (n=27), following antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions.Proportions of IL-7R+ CD4+ or CD8+ T-cells correlated positively with CD4+ T-cell counts and proportions of central memory and naïve CD4+ and CD8+ T-cells pre-ART (all r>0.50 and p<0.05), however the former negatively correlated with CD4+ T-cell counts fold-increase on ART in non-C-IRIS but not C-IRIS patients. Higher frequencies of activated monocytes (CD14+CD86+ or CD14+HLA-DR+; p≤0.038) were also observed in C-IRIS compared to non-C-IRIS patients and those who failed to clear cryptococci from cerebrospinal fluid pre-ART had higher levels of activated monocytes (CD14+HLA-DR+, p=0.017) compared to those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS (HR=1.055 [1.013-1.098]; p=0.009).In contrast to non-C-IRIS patients, C-IRIS patients displayed a lack of association between proportions of IL-7R+ T-cells and several markers of T-cell homeostasis. They also exhibited higher monocyte activation linked to CSF cryptococcal culture positivity pre-ART. These data suggest a role for IL-7/IL-7R signaling pathway dysregulation in the pathogenesis of C-IRIS, possibly linked to monocyte activation and residual pathogen burden pre-ART.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.