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

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.

Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection

“…In support of this idea the choroid plexus was recently shown to harbor JCPyV in patients [129]. JCPyV has also been detected associated with EVs purified from PML patient plasma, serum, and CSF [130]. This presents another possible, non-mutually exclusive mode of viral dissemination in the CNS.…”

“…At the same time, we must still consider the EV associated viral population that may play important roles in vivo [90,187]. JCPyV can exist in both nonenveloped and quasi-enveloped forms within a host and ignoring either population of JCPyV reduces the chances of discovering effective therapeutics for preventing and treating JCPyV-induced disease [130,188]. Overall, the association of nonenveloped viruses and extracellular vesicles blurs the line between enveloped vs. nonenveloped classification.…”

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…Treatment against the JCPyV virus also involves targeting EVs. For instance, teriflunomide, an MS drug, targets the EV-associated JCPyV, and a decrease in viral burden was reported in the CSF and the plasma . Thus, EVs play pleiotropic roles in PML pathogenesis and treatment, most of which still remain underexplored.…”

In vitro evaluation of the activity of teriflunomide against SARS-CoV-2 and the human coronaviruses 229E and OC43

“…In addition, preclinical studies have suggested that teriflunomide exerts inhibitory activity against a range of viruses. Among DNA viruses, teriflunomide has been shown to inhibit virion assembly of herpes simplex virus-1 [ 3 ], lytic reactivation and replication of Epstein–Barr virus [ 4 ], replication and early gene expression in BK polyomavirus [ 5 ], and infection and spread of John Cunningham polyomavirus [ 6 ]. Teriflunomide also disrupted the abnormal proliferation of T cells that occurs with infection by the retrovirus human T-lymphotropic virus-1 [ 7 ], and reduced production of the RNA viruses human respiratory syncytial virus [ 8 ] and Junín virus [ 9 ].…”