Journal Article

Teriflunomide Inhibits JCPyV Infection and Spread in Glial Cells and Choroid Plexus Epithelial Cells

Gretchen V. Gee, Bethany A. O’Hara, Igor J. Koralnik, Charlotte Nyblade, Alex Lublin, Chris Nieves, Timothy J. Turner, Sheila A. Haley, Xin Dang, Walter J. Atwood, Barbara A. Hanson, Jenna Morris-Love, Jeffrey M. Chavin

2021

Overview

Several classes of immunomodulators are used for treating relapsing-remitting multiple sclerosis (RRMS). Most of these disease-modifying therapies, except teriflunomide, carry the risk of progressive multifocal leukoencephalopathy (PML), a severely debilitating, often fatal virus-induced demyelinating disease. Because teriflunomide has been shown to have antiviral activity against DNA viruses, we investigated whether treatment of cells with teriflunomide inhibits infection and spread of JC polyomavirus (JCPyV), the causative agent of PML. Treatment of choroid plexus epithelial cells and astrocytes with teriflunomide reduced JCPyV infection and spread. We also used droplet digital PCR to quantify JCPyV DNA associated with extracellular vesicles isolated from RRMS patients. We detected JCPyV DNA in all patients with confirmed PML diagnosis (n = 2), and in six natalizumab-treated (n = 12), two teriflunomide-treated (n = 7), and two nonimmunomodulated (n = 2) patients. Of the 21 patients, 12 (57%) had detectable JCPyV in either plasma or serum. CSF was uniformly negative for JCPyV. Isolation of extracellular vesicles did not increase the level of detection of JCPyV DNA versus bulk unprocessed biofluid. Overall, our study demonstrated an effect of teriflunomide inhibiting JCPyV infection and spread in glial and choroid plexus epithelial cells. Larger studies using patient samples are needed to correlate these in vitro findings with patient data.

• Publisher: MDPI AG,MDPI
• Subject: Antigens / Antiviral drugs / Astrocytes / Astrocytes - drug effects / Astrocytes - virology / autoimmunity / Cell growth / Cell Line / choroid plexus / Choroid Plexus - drug effects / Choroid Plexus - virology / Chromatography / Crotonates / Crotonates - pharmacology / Dehydrogenases / Demyelinating Diseases / Demyelinating Diseases - drug therapy / Demyelinating Diseases - pathology / Demyelinating Diseases - virology / demyelination / DNA Viruses / DNA Viruses - drug effects / DNA Viruses - pathogenicity / Drug dosages / Encephalitis / Epithelial Cells / Epithelial Cells - drug effects / Epithelial Cells - virology / extracellular vesicle / Extracellular Vesicles / Extracellular Vesicles - drug effects / Extracellular Vesicles - virology / Genomes / glia / Humans / Hydroxybutyrates / Hydroxybutyrates - pharmacology / Immunologic Factors / Immunologic Factors - adverse effects / Immunologic Factors - therapeutic use / Immunology and Infectious Disease / Infections / JC Virus / JC Virus - drug effects / JC Virus - pathogenicity / Laboratories / Leukoencephalopathy, Progressive Multifocal / Leukoencephalopathy, Progressive Multifocal - chemically induced / Leukoencephalopathy, Progressive Multifocal - drug therapy / Leukoencephalopathy, Progressive Multifocal - pathology / Leukoencephalopathy, Progressive Multifocal - virology / Metabolism / Monoclonal antibodies / multiple sclerosis / Multiple Sclerosis, Relapsing-Remitting / Multiple Sclerosis, Relapsing-Remitting - drug therapy / Multiple Sclerosis, Relapsing-Remitting - genetics / Multiple Sclerosis, Relapsing-Remitting - pathology / Multiple Sclerosis, Relapsing-Remitting - virology / Nervous System Diseases / Neuroglia / Neuroglia - drug effects / Neuroglia - virology / neuroinflammation / Nitriles / Nitriles - pharmacology / Patients / Plasma / polyomavirus / Software / Toluidines / Toluidines - pharmacology / Viral infections / Virus Diseases / Virus Diseases - drug therapy / Virus Diseases - genetics / Virus Diseases - virology / Viruses