2. Academic Validation
  3. Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance

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

  • Antiviral Res. 2022 Jan;197:105224. doi: 10.1016/j.antiviral.2021.105224.
Steve Leumi 1,  Mingzhe Guo 2,  Jie Lu 3,  Zhaoning Wang 4,  Tianyu Gan 1,  Lin Han 5,  Jackline Ngari 1,  Yimin Tong 6,  Xiaogang Xiang 3,  Qing Xie 3,  Lanfeng Wang 4,  Jin Zhong 7
Affiliations

Affiliations

  • 1 Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; ShanghaiTech University, Shanghai, 201210, China.
  • 3 Department of Infectious Disease, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4 University of Chinese Academy of Sciences, Beijing, 100049, China; The Center for Microbes, Development and Heath, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 5 Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; ShanghaiTech University, Shanghai, 201210, China.
  • 6 Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 7 Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; ShanghaiTech University, Shanghai, 201210, China. Electronic address: jzhong@ips.ac.cn.
PMID: 34864126 DOI: 10.1016/j.antiviral.2021.105224
Abstract

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) subgenomic 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.

Keywords

Direct-acting antivirals; Genotype 1b; Hepatitis C virus; Resistance-associated substitutions; Sofosbuvir; Viral fitness.

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