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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.

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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Scriven JE, Graham LM, Schutz C, Scriba TJ, Wilkinson KA, Wilkinson RJ, Boulware DR, Urban BC, Meintjes G, Lalloo DG,


Scriven JE, Graham LM, Schutz C, Scriba TJ, Wilkinson KA, Wilkinson RJ, Boulware DR, Urban BC, Meintjes G, Lalloo DG, (click to view)

Scriven JE, Graham LM, Schutz C, Scriba TJ, Wilkinson KA, Wilkinson RJ, Boulware DR, Urban BC, Meintjes G, Lalloo DG,

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Journal of acquired immune deficiency syndromes (1999) 75(3) 299-307 doi 10.1097/QAI.0000000000001382

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 CD4CD8 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 CD4CD8 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.

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