{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T23:11:01Z","timestamp":1779923461240,"version":"3.53.1"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21430713900"],"award-info":[{"award-number":["21430713900"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012247","name":"Program of Shanghai Academic Research Leader","doi-asserted-by":"publisher","award":["XDB29010205"],"award-info":[{"award-number":["XDB29010205"]}],"id":[{"id":"10.13039\/501100012247","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatitis C virus (HCV) infection remains a challenge to human public health despite the development of highly effective direct\u2010acting antivirals (DAAs). Sofosbuvir (SOF), a key component in most DAA\u2010based anti\u2010HCV cocktail regimens, is a potent viral RNA polymerase (NS5B) inhibitor with a high barrier to drug resistance. The serine\u2010to\u2010threonine mutation at NS5B 282 (S282T) confers the SOF resistance, but severely impairs viral replication in most HCV genotypes (GTs) and cannot be stably maintained after the termination of the SOF\u2010based therapies. In this study, we first developed a new HCV GT\u20106a subgenomic replicon PR58D6. Next, we selected SOF\u2010resistant PR58D6 variants by culturing the replicon cells in the presence of SOF. Interestingly, unlike many other HCV replicons which require additional mutations to compensate for the S282T\u2010inducing fitness loss, S282T alone in PR58D6 is genetically stable and confers the SOF resistance without significantly impairing viral replication. Furthermore, we showed that amino acid residue at NS5B 74 (R74) and 556 (D556) which are conserved in GT 6a HCV contribute to efficient replication of PR58D6 containing S282T. Finally, we showed that the G556D mutation in NS5B could rescue the replication deficiency of the S282T in JFH1, a GT\u20102a replicon. In conclusion, we showed that a novel GT\u20106a HCV replicon may easily render SOF resistance, which may call for attention to potential drug resistance during DAA therapies of HCV GT\u20106a patients.<\/jats:p>","DOI":"10.1002\/jmv.29103","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T11:58:23Z","timestamp":1695038303000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Construction and characterization of a new hepatitis C virus genotype 6a subgenomic replicon that is prone to render the sofosbuvir resistance"],"prefix":"10.1002","volume":"95","author":[{"given":"Chaolun","family":"Liu","sequence":"first","affiliation":[{"name":"Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"},{"name":"School of Life Science and Technology ShanghaiTech University 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