HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses

David B. Meya; Samuel Okurut; Godfrey Zziwa; Stephen Cose; David R. Boulware; Edward N. Janoﬀ

doi:10.3390/jof5020042

HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses

David B. Meya, Samuel Okurut, Godfrey Zziwa, Stephen Cose, David R. Boulware, Edward N. Janoﬀ

Medicine - Infectious Disease and International Medicine

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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.

Original language	English (US)
Article number	42
Journal	Journal of Fungi
Volume	5
Issue number	2
DOIs	https://doi.org/10.3390/jof5020042
State	Published - Jun 2019

Bibliographical note

Funding Information:
Acknowledgments: We thank Abdu Musubire, Nabeta Henry, Joshua Rhein, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Radha Rajasingham, Catherine Nanteza, Richard Kwizera, and Darlisha Williams for patient care. We thank Tihana Bicanic, Lewis Haddow, and Jason Baker for generously serving on the external IRIS adjudication committee. We also thank the institutional support from the Infectious Diseases Institute, specifically Alex Coutinho and Keith McAdam. We also thank Britta Flach and Alison Taylor from Makerere University Walter Reed Project for using the Laboratory at Walter Reed in Kampala. We thank Brent Palmer and Harsh Pratap (University of Colorado Denver, Denver Veterans Affairs Medical Center) for their help with flow cytometry data analysis and interpretation.

Funding Information:
This work was funded by the Wellcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM) and the DELTAS Africa Initiative grant # DEL-15-011 to THRiVE-2. 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) with funding from theWellcome Trust grant # 107742/Z/15/Z and the UK government. The views expressed in this publication are those of the authors (s) and not necessarily those of AAS, NEPAD, Wellcome Trust, or the UK government. The clinical cohorts were supported in part by the National Institutes of Health (R01AI078934, U01AI089244, R01AI108479, K24AI096925, T32AI055433 DBM, DRB) and (R01AI108479l to ENJ); the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service (I01CX001464; ENJ). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
Funding: This work was funded by the Wellcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM) and the DELTAS Africa Initiative grant # DEL-15–011 to THRiVE-2. 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) with funding from the Wellcome Trust grant # 107742/Z/15/Z and the UK government. The views expressed in this publication are those of the authors (s) and not necessarily those of AAS, NEPAD, Wellcome Trust, or the UK government. The clinical cohorts were supported in part by the National Institutes of Health (R01AI078934, U01AI089244, R01AI108479, K24AI096925, T32AI055433 DBM, DRB) and (R01AI108479l to ENJ); the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service (I01CX001464; ENJ). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Adaptive immune response
CD4 T cells
CD8 T cells
Cryptococcal meningitis
Cryptococcus
HIV
IRIS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/jof5020042

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@article{046585119f144f36a74b7c4a440c0169,

title = "HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses",

abstract = "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.",

keywords = "Adaptive immune response, CD4 T cells, CD8 T cells, Cryptococcal meningitis, Cryptococcus, HIV, IRIS",

author = "Meya, {David B.} and Samuel Okurut and Godfrey Zziwa and Stephen Cose and Boulware, {David R.} and Janoﬀ, {Edward N.}",

note = "Funding Information: Acknowledgments: We thank Abdu Musubire, Nabeta Henry, Joshua Rhein, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Radha Rajasingham, Catherine Nanteza, Richard Kwizera, and Darlisha Williams for patient care. We thank Tihana Bicanic, Lewis Haddow, and Jason Baker for generously serving on the external IRIS adjudication committee. We also thank the institutional support from the Infectious Diseases Institute, specifically Alex Coutinho and Keith McAdam. We also thank Britta Flach and Alison Taylor from Makerere University Walter Reed Project for using the Laboratory at Walter Reed in Kampala. We thank Brent Palmer and Harsh Pratap (University of Colorado Denver, Denver Veterans Affairs Medical Center) for their help with flow cytometry data analysis and interpretation. Funding Information: This work was funded by the Wellcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM) and the DELTAS Africa Initiative grant # DEL-15-011 to THRiVE-2. 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) with funding from theWellcome Trust grant # 107742/Z/15/Z and the UK government. The views expressed in this publication are those of the authors (s) and not necessarily those of AAS, NEPAD, Wellcome Trust, or the UK government. The clinical cohorts were supported in part by the National Institutes of Health (R01AI078934, U01AI089244, R01AI108479, K24AI096925, T32AI055433 DBM, DRB) and (R01AI108479l to ENJ); the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service (I01CX001464; ENJ). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Funding Information: Funding: This work was funded by the Wellcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM) and the DELTAS Africa Initiative grant # DEL-15–011 to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS){\textquoteright}s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa{\textquoteright}s Development Planning and Coordinating Agency (NEPAD) with funding from the Wellcome Trust grant # 107742/Z/15/Z and the UK government. The views expressed in this publication are those of the authors (s) and not necessarily those of AAS, NEPAD, Wellcome Trust, or the UK government. The clinical cohorts were supported in part by the National Institutes of Health (R01AI078934, U01AI089244, R01AI108479, K24AI096925, T32AI055433 DBM, DRB) and (R01AI108479l to ENJ); the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service (I01CX001464; ENJ). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2019",

month = jun,

doi = "10.3390/jof5020042",

language = "English (US)",

volume = "5",

journal = "Journal of Fungi",

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TY - JOUR

T1 - HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses

AU - Meya, David B.

AU - Okurut, Samuel

AU - Zziwa, Godfrey

AU - Cose, Stephen

AU - Boulware, David R.

AU - Janoﬀ, Edward N.

N1 - Funding Information: Acknowledgments: We thank Abdu Musubire, Nabeta Henry, Joshua Rhein, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Radha Rajasingham, Catherine Nanteza, Richard Kwizera, and Darlisha Williams for patient care. We thank Tihana Bicanic, Lewis Haddow, and Jason Baker for generously serving on the external IRIS adjudication committee. We also thank the institutional support from the Infectious Diseases Institute, specifically Alex Coutinho and Keith McAdam. We also thank Britta Flach and Alison Taylor from Makerere University Walter Reed Project for using the Laboratory at Walter Reed in Kampala. We thank Brent Palmer and Harsh Pratap (University of Colorado Denver, Denver Veterans Affairs Medical Center) for their help with flow cytometry data analysis and interpretation. Funding Information: This work was funded by the Wellcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM) and the DELTAS Africa Initiative grant # DEL-15-011 to THRiVE-2. 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) with funding from theWellcome Trust grant # 107742/Z/15/Z and the UK government. The views expressed in this publication are those of the authors (s) and not necessarily those of AAS, NEPAD, Wellcome Trust, or the UK government. The clinical cohorts were supported in part by the National Institutes of Health (R01AI078934, U01AI089244, R01AI108479, K24AI096925, T32AI055433 DBM, DRB) and (R01AI108479l to ENJ); the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service (I01CX001464; ENJ). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Funding Information: Funding: This work was funded by the Wellcome Trust (Training Health Researchers into Vocational Excellence (THRiVE) in East Africa, grant number 087540-DBM) and the DELTAS Africa Initiative grant # DEL-15–011 to THRiVE-2. 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) with funding from the Wellcome Trust grant # 107742/Z/15/Z and the UK government. The views expressed in this publication are those of the authors (s) and not necessarily those of AAS, NEPAD, Wellcome Trust, or the UK government. The clinical cohorts were supported in part by the National Institutes of Health (R01AI078934, U01AI089244, R01AI108479, K24AI096925, T32AI055433 DBM, DRB) and (R01AI108479l to ENJ); the GlaxoSmithKline Collaborative Investigator Research Award (CIRA) and the Veterans Affairs Research Service (I01CX001464; ENJ). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - Adaptive immune response

KW - CD4 T cells

KW - CD8 T cells

KW - Cryptococcal meningitis

KW - Cryptococcus

KW - HIV

KW - IRIS

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HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome Is Associated with Aberrant T Cell Function and Increased Cytokine Responses

Abstract

Bibliographical note

Keywords

UN SDGs

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