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01-12-2016

Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients

Authors: Anat Achiron, Gadi Miron, Rina Zilkha-Falb, David Magalashvili, Mark Dolev, Yael Stern, Michael Gurevich

Published in: Journal of NeuroVirology | Issue 6/2016

Abstract

Estimating the individual risk for the development of progressive multifocal leukoencephalopathy (PML) in anti-John Cunningham virus (JCV) antibody-negative patients with multiple sclerosis (MS) treated with natalizumab is a major challenge. A serological conversion occurring under treatment from anti-JCV antibody-negative to positive status may significantly increase this risk. We investigated changes in peripheral blood cells’ gene expression induced by natalizumab treatment in anti-JCV antibody-negative MS patients and tested blood transcriptional profile that characterizes patients predisposed to antibody switch under natalizumab treatment. After 3 years of natalizumab treatment, 24.6 % of anti-JCV antibody-negative MS patients switched to become anti-JCV antibody-positive (JCV switchers). Natalizumab induced 946 and 1186 significantly differentiating genes in JCV switchers and non-switchers, respectively. In JCV switchers, the signature was enriched by over-expression of genes associated with the first stages of viral entry to host cells including macropinocytosis (p = 1.82E−06), virus entry via endocytosis (p = 1.60E−06), clathrin-mediated endocytosis (p = 1.13E−04), and caveolar-mediated endocytosis (p = 4.50E−04) pathways. Further analysis to identify pre-existing transcriptional differences that characterize future JCV switchers prior to treatment initiation also demonstrated a transcriptional signature enriched by similar viral entry mechanisms. These findings, verified in an additional independent cohort of natalizumab-treated patients, could lead to future identification of patients that remain anti-JCV antibody-negative thus allowing safe continuation of treatment, as well as the development of future targeted therapeutic interventions to reduce the risk of PML.

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Title: Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients
Authors: Anat Achiron
Gadi Miron
Rina Zilkha-Falb
David Magalashvili
Mark Dolev
Yael Stern
Michael Gurevich
Publication date: 01-12-2016
Publisher: Springer International Publishing
Published in: Journal of NeuroVirology / Issue 6/2016
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-016-0445-4

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