Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance

doi:10.1016/j.antiviral.2021.105224

	Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance
	Leumi, Steve 1,2; Guo, Mingzhe1,2,3 ; Lu, Jie 4; Wang, Zhaoning 2,5; Gan, Tianyu 1,2; Han, Lin1,3 ; Ngari, Jackline 1,2; Tong, Yimin 1; Xiang, Xiaogang 4; Xie, Qing 4; Wang, Lanfeng 2,5; Zhong, Jin1,2,3,6
	2022-01
发表期刊	ANTIVIRAL RESEARCH (IF:4.5[JCR-2023],5.0[5-Year])
ISSN	0166-3542
EISSN	1872-9096
卷号	197
发表状态	已发表
DOI	10.1016/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
URL	查看原文
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
引用统计	正在获取...
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
推荐引用方式 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).