Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance
2022-01
发表期刊ANTIVIRAL RESEARCH (IF:4.5[JCR-2023],5.0[5-Year])
ISSN0166-3542
EISSN1872-9096
卷号197
发表状态已发表
DOI10.1016/j.antiviral.2021.105224
摘要Despite the excellent antiviral potency of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), emergence of drug-resistant viral mutations remains a potential challenge. Sofobuvir (SOF), a nucleotide analog targeting HCV NS5B -RNA-dependent RNA polymerase (RdRp), constitutes a key component of many anti-HCV cocktail regimens and confers a high barrier for developing drug resistance. The serine to threonine mutation at the amino acid position 282 of NS5B (S282T) is the mostly documented SOF resistance-associated substitution (RAS), but severely hampers the virus fitness. In this study, we first developed new genotype 1b (GT1b) sub-genomic replicon cells, denoted PR52D4 and PR52D9, directly from a GT1b clinical isolate. Next, we obtained SOF-resistant and replication-competent PR52D4 replicon by culturing the replicon cells in the presence of SOF. Sequencing analysis showed that the selected replicon harbored two mutations K74R and S282T in NS5B. Reverse genetics analysis showed that while PR52D4 consisting of either single mutation K74R or S282T could not replicate efficiently, the engineering of the both mutations led to a replication-competent and SOF-resistant PR52D4 replicon. Furthermore, we showed that the K74R mutation could also rescue the replication deficiency of the S282T mutation in Con1, another GT1b replicon as well as in JFH1, a GT2a replicon. Structural modeling analysis suggested that K74R might help maintain an active catalytic conformation of S282T by engaging with Y296. In conclusion, we identified the combination of two NS5B mutations S282T and K74R as a novel RAS that confers a substantial resistance to SOF while retains the HCV replication capacity.
关键词Hepatitis C virus Genotype 1b Sofosbuvir Direct-acting antivirals Viral fitness Resistance-associated substitutions
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收录类别SCI ; SCIE
语种英语
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDB29010205] ; International Science and Technology Cooperation Program of Shanghai Municipality[21430713900] ; National Natural Science Foundation of China[32070944,31770189,31770816]
WOS研究方向Pharmacology & Pharmacy ; Virology
WOS类目Pharmacology & Pharmacy ; Virology
WOS记录号WOS:000795710000005
出版者ELSEVIER
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/187890
专题生命科学与技术学院_博士生
生命科学与技术学院_特聘教授组_钟劲组
通讯作者Zhong, Jin
作者单位
1.Chinese Acad Sci, Inst Pasteur Shanghai, Unit Viral Hepatitis, CAS Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.ShanghaiTech Univ, Shanghai 201210, Peoples R China
4.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Infect Dis, Sch Med, Shanghai, Peoples R China
5.Chinese Acad Sci, Inst Pasteur Shanghai, Ctr Microbes, CAS Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China
6.Chinese Acad Sci, Inst Pasteur Shanghai, Shanghai 200031, Peoples R China
通讯作者单位上海科技大学
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GB/T 7714
Leumi, Steve,Guo, Mingzhe,Lu, Jie,et al. Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance[J]. ANTIVIRAL RESEARCH,2022,197.
APA Leumi, Steve.,Guo, Mingzhe.,Lu, Jie.,Wang, Zhaoning.,Gan, Tianyu.,...&Zhong, Jin.(2022).Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance.ANTIVIRAL RESEARCH,197.
MLA Leumi, Steve,et al."Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance".ANTIVIRAL RESEARCH 197(2022).
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