复制子
NS5B
病毒学
丙型肝炎病毒
亚基因组mRNA
索福斯布维尔
生物
病毒复制
抗性突变
基因型
病毒
NS5A型
突变
肝炎病毒
遗传学
逆转录酶
核糖核酸
基因
基因组
利巴韦林
作者
Chaolun Liu,Mingzhe Guo,Li Han,Jie Lu,Xiaogang Xiang,Qing Xie,Janin Nouhin,Veasna Duong,Yimin Tong,Jin Zhong
摘要
Hepatitis C virus (HCV) infection remains a challenge to human public health despite the development of highly effective direct-acting antivirals (DAAs). Sofosbuvir (SOF), a key component in most DAA-based anti-HCV cocktail regimens, is a potent viral RNA polymerase (NS5B) inhibitor with a high barrier to drug resistance. The serine-to-threonine 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-based therapies. In this study, we first developed a new HCV GT-6a subgenomic replicon PR58D6. Next, we selected SOF-resistant 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-inducing 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-2a replicon. In conclusion, we showed that a novel GT-6a HCV replicon may easily render SOF resistance, which may call for attention to potential drug resistance during DAA therapies of HCV GT-6a patients.
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