HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses
by
David B. Meya 1,2,3,*
, Samuel Okurut 1, Godfrey Zziwa 4, Stephen Cose 5,6, David R. Boulware 2 and Edward N. Janoff 7
, Samuel Okurut 1, Godfrey Zziwa 4, Stephen Cose 5,6, David R. Boulware 2 and Edward N. Janoff 7
1
Infectious Diseases Institute, Makerere University, Kampala P.O. Box 22418, Uganda
2
Department of Medicine, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, MN 55455, USA
3
School of Medicine, College of Health Sciences, Makerere University, Kampala P.O. Box 7072, Uganda
4
Research Department, Makerere University Walter Reed Project, Plot 42, Nakasero Road, Kampala P.O. Box 1624, Uganda
5
Clinical Research Department, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK
6
MRC/UVRI and LSHTM Uganda Research Unit, Plot 51–59 Nakiwogo Road, Entebbe P.O.Box 49, Uganda
7
Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado, Denver, Aurora, CO 80045, USA
*
Author to whom correspondence should be addressed.
J. Fungi 2019, 5(2), 42; https://doi.org/10.3390/jof5020042
Received: 5 April 2019 / Revised: 24 April 2019 / Accepted: 29 April 2019 / Published: 23 May 2019
(This article belongs to the Special Issue Fungal Infections of the Central Nervous System)
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.
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Keywords:
cryptococcal meningitis; Cryptococcus; HIV; CD4 T cells; CD8 T cells; adaptive immune response; IRIS
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MDPI and ACS Style
Meya, D.B.; Okurut, S.; Zziwa, G.; Cose, S.; Boulware, D.R.; Janoff, E.N. HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses. J. Fungi 2019, 5, 42.
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