{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T23:08:58Z","timestamp":1779923338577,"version":"3.53.1"},"reference-count":15,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T00:00:00Z","timestamp":1702684800000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Among its 8 genotypes (GT), GT3 has a relatively lower sustained virological response to highly effective direct\u2010acting antiviral agents (DAA). Sofosbuvir (SOF), an anti\u2010NS5B polymerase inhibitor, is a core component of many anti\u2010HCV DAA cocktail regimens, and its resistant mutations are rare in clinics because these mutations usually severely impair the NS5B polymerase activity, including a mutation S282T in NS5B, the most frequently reported SOF\u2010resistant mutation. In this study, we selected SOF\u2010resistant variants of a previously developed GT3 subgenomic replicon (PR87A7). Two mutations were identified in the viral genome of SOF\u2010resistant PR87A7 variants, Q606R in nontargeted NS3 and S282T in targeted N5SB. We demonstrated that Q606R could rescue the replication defect of S282T in PR87A7, and the resulting double mutant confers the SOF resistance. Finally, we showed that NS3\u2010606R could not compensate for the replication defect of S282T in other GTs. In conclusion, we identified a novel GT3\u2010specific combination of two mutations that confers SOF resistance. Our result calls for attention to potential mutations that may arise in nontargeted viral proteins during the SOF\u2010based DAA treatment of chronic HCV.<\/jats:p>","DOI":"10.1002\/jmv.29290","type":"journal-article","created":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T12:05:35Z","timestamp":1702728335000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification and characterization of Sofosbuvir\u2010resistant mutations of hepatitis C virus genotype 3a replicon"],"prefix":"10.1002","volume":"95","author":[{"given":"Jackline Wangu","family":"Ngari","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"},{"name":"Savaid Medical School University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Leumi","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"},{"name":"Savaid Medical School University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Han","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"},{"name":"Savaid Medical School University of Chinese Academy of Sciences  Beijing China"},{"name":"School of Life Science and Technology ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaolun","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"},{"name":"School of Life Science and Technology ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Tong","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3554-1275","authenticated-orcid":false,"given":"Jin","family":"Zhong","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences  Shanghai China"},{"name":"Savaid Medical School University of Chinese Academy of Sciences  Beijing China"},{"name":"School of Life Science and Technology ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,16]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"WHO.Hepatitis C.2023. 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