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Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome Is Associated With Dysregulation of IL-7/IL-7 Receptor Signaling Pathway in T Cells and Monocyte Activation

Akilimali, Ngomu Akeem, MSc, PhDa,b; Muema, Daniel M., BPharm, PhDa,b,c; Specht, Charles, PhDd; Chang, Christina C., MD, PhDa,e; Moosa, Mahomed-Yunus S., MBChB, FCP(SA); PhDa,f; Levitz, Stuart M., MDd; Lewin, Sharon R., FRACP, PhD, FAHMSg; French, Martyn A., MB ChB, MD, FRACPh,i; Ndung'u, Thumbi, BVM, PhDa,b,j,k

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 15, 2019 - Volume 80 - Issue 5 - p 596–604
doi: 10.1097/QAI.0000000000001946
Translational Research

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.

aAfrica Health Research Institute (AHRI), Durban, South Africa;

bHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal (UKZN), Durban, South Africa;

cWellcome Trust Research Programme, Kenya Medical Research Institute, Centre for Geographic Medicine Research-Coast, Kilifi, Kenya;

dDivision of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA;

eDepartment of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia;

fDepartment of Infectious Diseases, UKZN, Durban, South Africa;

gThe Peter Doherty Institute for Infection and Immunity, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia;

hMedical School and School of Biomedical Sciences, University of Western Australia, Perth, Australia;

iDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia;

jMax Planck Institute for Infection Biology, Berlin, Germany; and

kThe Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard University, Cambridge, MA.

Correspondence to: Thumbi Ndung'u, BVM, PhD, Africa Health Research Institute (AHRI), University of KwaZulu-Natal, K-RITH Tower Building, Level 5, 719 Umbilo Road, Durban 4013, South Africa 4623 (e-mail:

Supported by REACH Initiative (Research and Education in HIV/AIDS for Resource Poor Countries) (M.A.F.) and Pfizer Neuroscience Grant (NS052.10—C.C.C.). C.C.C. is supported by the Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship APP1092160. M.A.F. was supported by NHMRC grant 510448. S.R.L. is a NHMRC practitioner fellow APP1042654. T.N. was supported by grants from the Howard Hughes Medical Institute and by the South African Department of Science and Technology/National Research Foundation Research Chairs Initiative. Additional support for this study was provided by the Victor Daitz Foundation. This work was also supported in part through the sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [grant # DEL-15-006]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)'s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [grant # 107752/Z/15/Z] and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK government.

Presented in part at 9th IAS Conference on HIV Science; July 23–26, 2017; Paris, France.

The authors have no funding or conflicts of interest to disclose.

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Received July 18, 2018

Accepted December 03, 2018

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