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

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

doi:10.3390/ijms22189809

Abstract

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.

Highlights

The JC polyomavirus (JCPyV)-induced disease progressive multifocal leukoencephalopathy (PML) was once an extremely rare event that occurred in the context of lymphoid cancers such as leukemia and Hodgkin’s disease [15,16]
In the early 1980s, PML emerged as a fatal complication of human immunodeficiency virus (HIV) infection and in 2005 it emerged as a fatal complication in patients with autoimmune disease being treated with powerful new immunomodulatory drugs [17,18,19,20,21,22,23]
Because teriflunomide has been shown to inhibit DNA viruses that require cell proliferation, we evaluated whether the lack of PML in teriflunomidetreated patients might be attributed to its antiviral activity

Summary

Introduction

The majority of human polyomaviruses cause long-term asymptomatic persistent infections in their host [1]. Several are associated with disease in immunocompromised or immunomodulated patients (JC polyomavirus [JCPyV], BK polyomavirus [BKPyV], Trichodysplasia spinulosa polyomavirus [TSPyV]) or with the development of cancer (Merkel cell polyomavirus [MCPyV]) [1]. JCPyV is the only member of the family to cause neurologic disease [2,3]. In the context of prolonged immunosuppression or prolonged treatment with powerful immunomodulators, JCPyV can give rise to an often fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML) [2,4]. Several immunomodulators used to treat patients with multiple sclerosis (MS)

Methods

Results

Conclusion