Journal
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
Volume 80, Issue 5, Pages 596-604Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAI.0000000000001946
Keywords
AIDS-induced cryptococcal meningitis; cryptococcosis-associated immune reconstitution inflammatory syndrome; T cells; monocytes; IL-7/IL-7 receptor signaling pathway; antigen-specific responses and immune activation
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Funding
- REACH Initiative (Research and Education in HIV/AIDS for Resource Poor Countries)
- Pfizer Neuroscience Grant [NS052.10]
- Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship [APP1092160]
- NHMRC [510448]
- Howard Hughes Medical Institute
- South African Department of Science and Technology/National Research Foundation Research Chairs Initiative
- Victor Daitz Foundation
- sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [DEL-15-006]
- Wellcome Trust [107752/Z/15/Z]
- UK government
- New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency)
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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 (CD14(+) CD86(+) 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.
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