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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>Mycophenolic acid (MPA) is commonly used in immunosuppressive regimens following solid organ transplantation. We demonstrate that MPA treatment reproducibly inhibits the replication of a range of viruses, including severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Mechanistically, we identified cellular guanosine triphosphate pool depletion as a key mediator of this antiviral effect. Strikingly, this inhibition can be overcome which was correlated with the emergence of three breakthrough mutations in the SARS-CoV-2 genome (S P812R, ORF3 Q185H, and E S6L). Subsequent analyses confirmed that the combination of these mutations conferred accelerated replication kinetics, higher viral titers, and more rapid onset of cytopathic effects, but not MPA resistance. Comparison of global transcriptional responses to infection highlighted dysregulation of specific cellular gene programs under MPA treatment prior to breakthrough mutation emergence. Together, these findings identify viral and host drivers of variant emergence under immunosuppression. They also advocate for close monitoring of immunosuppressed patients, where emergence of novel viral variants with a fitness advantage may arise.<\/jats:p>","DOI":"10.1073\/pnas.2500276122","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T15:40:02Z","timestamp":1752075602000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8962-9443","authenticated-orcid":false,"given":"Toni Luise","family":"Meister","sequence":"first","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum","place":["Bochum, Germany"]},{"name":"Institute for Infection Research and Vaccine Development, Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf","place":["Hamburg, Germany"]},{"name":"Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]},{"name":"German Centre for Infection Research (Deutsches Zentrum f\u00fcr Infektionsforschung), Partner Site Hamburg-L\u00fcbeck-Borstel-Riems","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4632-525X","authenticated-orcid":false,"given":"Maximilian K.","family":"Nocke","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum","place":["Bochum, Germany"]},{"name":"Department of Translational and Computational Infection Research, Ruhr University Bochum","place":["Bochum, Germany"]},{"name":"European Virus Bioinformatics Centre","place":["Jena, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Heinen","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L.","family":"Burkard","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Br\u00fcggemann","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Westhoven","sequence":"additional","affiliation":[{"name":"Department for Molecular and Medical Virology, Ruhr University Bochum","place":["Bochum, Germany"]},{"name":"Leibniz Institute of Virology - 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