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The CSF immune response in HIV-1-associated cryptococcal meningitis: macrophage activation, correlates of disease severity, and effect of antiretroviral therapy

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Title: The CSF immune response in HIV-1-associated cryptococcal meningitis: macrophage activation, correlates of disease severity, and effect of antiretroviral therapy
Authors: Scriven, JE
Graham, LM
Schutz, C
Scriba, TJ
Wilkinson, KA
Wilkinson, RJ
Boulware, DR
Urban, BC
Meintjes, G
Lalloo, DG
Item Type: Journal Article
Abstract: Background: Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). Methodology: We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). Findings: CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14+ and 35% CD14− monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4+, CD8+, and CD4−CD8− T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4−CD8− T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. Conclusions: Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.
Issue Date: 31-Mar-2017
Date of Acceptance: 31-Jan-2017
URI: http://hdl.handle.net/10044/1/51338
DOI: https://dx.doi.org/10.1097/QAI.0000000000001382
ISSN: 1525-4135
Publisher: Lippincott, Williams & Wilkins
Start Page: 299
End Page: 307
Journal / Book Title: JAIDS-Journal of Acquired Immune Deficiency Syndromes
Volume: 75
Issue: 3
Replaces: http://hdl.handle.net/10044/1/50700
10044/1/50700
10044/1/46156
http://hdl.handle.net/10044/1/46156
Copyright Statement: © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 104803/Z/14/ZR
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
Infectious Diseases
Cryptococcus
immune response
alternatively activated macrophages
flow cytometry
fungal burden
raised intracranial pressure
mortality
CEREBROSPINAL-FLUID PRESSURE
ALTERNATIVE ACTIVATION
FLOW-CYTOMETRY
FUNGAL BURDEN
IFN-GAMMA
NEOFORMANS
INFECTION
HIV
CELLS
EXPRESSION
Virology
Publication Status: Published
Open Access location: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469563/
Appears in Collections:Department of Medicine



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