Ngomu Akeem Akilimali1,2, Daniel M Muema1,2,3, Charles Specht4, Christina C Chang1,5, Mahomed-Yunus S Moosa1,6, Stuart M Levitz4, Sharon R Lewin7, Martyn A French8,9, Thumbi Ndungʼu1,2,10,11. 1. Africa Health Research Institute (AHRI), Durban, South Africa. 2. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal (UKZN), Durban, South Africa. 3. Wellcome Trust Research Programme, Kenya Medical Research Institute, Centre for Geographic Medicine Research-Coast, Kilifi, Kenya. 4. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA. 5. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia. 6. Department of Infectious Diseases, UKZN, Durban, South Africa. 7. The Peter Doherty Institute for Infection and Immunity, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia. 8. Medical School and School of Biomedical Sciences, University of Western Australia, Perth, Australia. 9. Department of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia. 10. Max Planck Institute for Infection Biology, Berlin, Germany. 11. The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard University, Cambridge, MA.
Abstract
BACKGROUND: 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. METHOD: HIV-infected patients with cryptococcal meningitis who experienced C-IRIS (n = 27) were compared with CD4 T-cell count-matched counterparts without C-IRIS (n = 27), after antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions. RESULTS: Proportions of IL-7R+ CD4 or CD8 T cells correlated positively with CD4 T-cell counts and proportions of central memory and naive CD4 and CD8 T-cell 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 (CD14CD86 or CD14+HLA-DR+; P ≤ 0.038) were also observed in C-IRIS compared with non-C-IRIS patients, and those who failed to clear cryptococci from cerebrospinal fluid before ART had higher levels of activated monocytes (CD14+HLA-DR+, P = 0.017) compared with those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS [hazard ratio = 1.055 (1.013-1.098); P = 0.009]. CONCLUSION: 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 cerebrospinal fluid cryptococcal culture positivity before 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 before ART.
BACKGROUND: 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. METHOD:HIV-infectedpatients with cryptococcal meningitis who experienced C-IRIS (n = 27) were compared with CD4 T-cell count-matched counterparts without C-IRIS (n = 27), after antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions. RESULTS: Proportions of IL-7R+ CD4 or CD8 T cells correlated positively with CD4 T-cell counts and proportions of central memory and naive CD4 and CD8 T-cell 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-IRISpatients. Higher frequencies of activated monocytes (CD14CD86 or CD14+HLA-DR+; P ≤ 0.038) were also observed in C-IRIS compared with non-C-IRISpatients, and those who failed to clear cryptococci from cerebrospinal fluid before ART had higher levels of activated monocytes (CD14+HLA-DR+, P = 0.017) compared with those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS [hazard ratio = 1.055 (1.013-1.098); P = 0.009]. CONCLUSION: In contrast to non-C-IRISpatients, C-IRISpatients 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 cerebrospinal fluid cryptococcal culture positivity before 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 before ART.
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