{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:43:07Z","timestamp":1762508587494,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disease and Stroke","award":["R01NS43097","R35NS5271118"],"award-info":[{"award-number":["R01NS43097","R35NS5271118"]}]},{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"publisher","award":["Collaborative research agreement"],"award-info":[{"award-number":["Collaborative research agreement"]}],"id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006418","name":"Brown University","doi-asserted-by":"publisher","award":["Undergraduate research training awards"],"award-info":[{"award-number":["Undergraduate research training awards"]}],"id":[{"id":"10.13039\/100006418","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22189809","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T10:31:34Z","timestamp":1631269894000},"page":"9809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Teriflunomide Inhibits JCPyV Infection and Spread in Glial Cells and Choroid Plexus Epithelial Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Bethany A.","family":"O\u2019Hara","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gretchen V.","family":"Gee","sequence":"additional","affiliation":[{"name":"MassBiologics, University of Massachusetts Medical School, Worcester, MA 01601, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheila A.","family":"Haley","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4853-2175","authenticated-orcid":false,"given":"Jenna","family":"Morris-Love","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Nyblade","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Nieves","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara A.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Dang","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J.","family":"Turner","sequence":"additional","affiliation":[{"name":"Sanofi, Cambridge, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey M.","family":"Chavin","sequence":"additional","affiliation":[{"name":"Sanofi, Cambridge, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Lublin","sequence":"additional","affiliation":[{"name":"Sanofi, Cambridge, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor J.","family":"Koralnik","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-9073","authenticated-orcid":false,"given":"Walter J.","family":"Atwood","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1146\/annurev-virology-110615-042226","article-title":"Polyomavirus persistence","volume":"3","author":"Imperiale","year":"2016","journal-title":"Annu. Rev. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1146\/annurev-virology-101416-041439","article-title":"Progressive multifocal leukoencephalopathy: Endemic viruses and lethal brain disease","volume":"4","author":"Haley","year":"2017","journal-title":"Annu. Rev. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1515\/hsz-2016-0345","article-title":"The biology of JC polyomavirus","volume":"398","author":"Assetta","year":"2017","journal-title":"Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41582-020-00427-y","article-title":"Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease","volume":"17","author":"Cortese","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.msard.2017.01.006","article-title":"Classifying PML risk with disease modifying therapies","volume":"12","author":"Berger","year":"2017","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1097\/NEN.0000000000000005","article-title":"Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: A postmortem study","volume":"72","author":"Wuthrich","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1056\/NEJMoa0904267","article-title":"Asymptomatic reactivation of JC virus in patients treated with natalizumab","volume":"361","author":"Chen","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1056\/NEJMe058122","article-title":"Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences","volume":"353","author":"Berger","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102438","DOI":"10.1016\/j.msard.2020.102438","article-title":"Long-term safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis: Results from the TOWER extension study","volume":"46","author":"Miller","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1097\/01.tp.0000181149.76113.50","article-title":"Treatment of renal allograft polyoma BK virus infection with leflunomide","volume":"81","author":"Josephson","year":"2006","journal-title":"Transplantation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1056\/NEJM200503173521125","article-title":"Leflunomide for polyomavirus type BK nephropathy","volume":"352","author":"Williams","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.jneuroim.2013.10.003","article-title":"The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro","volume":"265","author":"Li","year":"2013","journal-title":"J. Neuroimmunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"O\u2019Hara, B.A., Morris-Love, J., Gee, G.V., Haley, S.A., and Atwood, W.J. (2020). JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008371"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00105-18","DOI":"10.1128\/JVI.00105-18","article-title":"Susceptibility of primary human choroid plexus epithelial cells and meningeal cells to infection by JC virus","volume":"92","author":"Gee","year":"2018","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/brain\/81.1.93","article-title":"Progressive multifocal leukoencephalopathy","volume":"81","author":"Astrom","year":"1958","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1056\/NEJM196110262651701","article-title":"Progressive multifocal leukoencephalopathy","volume":"265","author":"Richardson","year":"1961","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJM198212023072307","article-title":"Progressive multifocal leukoencephalopathy in a male homosexual with T-cell immune deficiency","volume":"307","author":"Miller","year":"1982","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1001\/archneur.1984.04050180102028","article-title":"Progressive multifocal leukoencephalopathy in a patient with acquired immune deficiency syndrome","volume":"41","author":"Bernick","year":"1984","journal-title":"Arch. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0733-8619(18)31105-8","article-title":"Progressive multifocal leukoencephalopathy","volume":"2","author":"Brooks","year":"1984","journal-title":"Neurol. Clin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1056\/NEJMc055235","article-title":"Natalizumab and progressive multifocal leukoencephalopathy","volume":"353","author":"Adelman","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_21","first-page":"1577","article-title":"Central nervous system infections with immunomodulatory therapies","volume":"21","author":"Williamson","year":"2015","journal-title":"Continuum. Minneap. Minn."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e235","DOI":"10.1212\/NXI.0000000000000235","article-title":"A link between long-term natalizumab dosing in MS and PML: Putting the puzzle together","volume":"3","author":"Major","year":"2016","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s13365-016-0427-6","article-title":"Reassessing the risk of natalizumab-associated PML","volume":"22","author":"Berger","year":"2016","journal-title":"J. Neurovirol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1136\/jnnp-2015-312940","article-title":"Extended interval dosing of natalizumab in multiple sclerosis","volume":"87","author":"Frohman","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/jcph.1737","article-title":"Modeling the efficacy of natalizumab in multiple sclerosis patients who switch from every-4-week dosing to extended-interval dosing","volume":"61","author":"Chang","year":"2021","journal-title":"J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1452","DOI":"10.1212\/WNL.0000000000008243","article-title":"Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing","volume":"93","author":"Ryerson","year":"2019","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1007\/s10072-019-03959-4","article-title":"Four cases of natalizumab-related PML: A less severe course in extended interval dosing?","volume":"40","author":"Scarpazza","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1007\/s13365-019-00753-y","article-title":"JC virus infection of meningeal and choroid plexus cells in patients with progressive multifocal leukoencephalopathy","volume":"25","author":"Corbridge","year":"2019","journal-title":"J. Neurovirol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1038\/ncomms3123","article-title":"Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma","volume":"4","author":"Grapp","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104435","DOI":"10.1016\/j.jcv.2020.104435","article-title":"Archetype JC polyomavirus DNA associated with extracellular vesicles circulates in human plasma samples","volume":"128","author":"Scribano","year":"2020","journal-title":"J. Clin. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102008","DOI":"10.1016\/j.msard.2020.102008","article-title":"Which is the best PML risk stratification strategy in natalizumab-treated patients affected by multiple sclerosis?","volume":"41","author":"Prezioso","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e00379-19","DOI":"10.1128\/mBio.00379-19","article-title":"JC polyomavirus uses extracellular vesicles to infect target cells","volume":"10","author":"Gee","year":"2019","journal-title":"mBio"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/acn3.51130","article-title":"Improving risk-stratification of natalizumab-associated PML","volume":"8","author":"Tugemann","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"579438","DOI":"10.3389\/fneur.2020.579438","article-title":"New algorithms improving PML risk stratification in MS patients treated with natalizumab","volume":"11","author":"Toboso","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_35","first-page":"9","article-title":"Propagation and assay of the JC virus","volume":"165","author":"Liu","year":"2001","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9809\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:00:42Z","timestamp":1760166042000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,10]]},"references-count":35,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22189809"],"URL":"https:\/\/doi.org\/10.3390\/ijms22189809","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,9,10]]}}}