The CSF Immune Response in HIV-1-Associated Cryptococcal Meningitis: Macrophage Activation, Correlates of Disease Severity, and Effect of Antiretroviral Therapy

James E E Scriven, Lisa M M Graham, Charlotte Schutz, Thomas J J Scriba, Katalin A A Wilkinson, Robert J J Wilkinson, David R R Boulware, Britta C C Urban, Graeme Meintjes, David G G Lalloo

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20 Scopus citations

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/L). 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 H 2 O) 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.

Original languageEnglish (US)
Pages (from-to)299-307
Number of pages9
JournalJournal of Acquired Immune Deficiency Syndromes
Volume75
Issue number3
DOIs
StatePublished - Jul 1 2017

Bibliographical note

Funding Information:
Supported by the Wellcome Trust through a training fellowship to J.E.S. (094013/B/10/Z). G.M. is supported by the Wellcome Trust (098316), the South African Medical Research Council and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (64787). C.S., D.R.B., and G.M. receive support from the National Institutes of Health (U01AI089244). R.J.W. receives funding from Medical research Council (U1175.02.002.00014.01), Wellcome Trust (104803), National Research Foundation of South Africa (96841), European Union (FP7-PEOPLE-2011-IRSES and FP7-HEALTH-F3-2012-305578). B.C.U. is supported by the Wellcome Trust (079082). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone.

Publisher Copyright:
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.

Keywords

  • Cryptococcus
  • alternatively activated macrophages
  • flow cytometry
  • fungal burden
  • immune response
  • mortality
  • raised intracranial pressure

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