2. Academic Validation
  3. Construction and characterization of Genotype-3 hepatitis C virus replicon revealed critical genotype-3-specific polymorphism for drug resistance and viral fitness

Construction and characterization of Genotype-3 hepatitis C virus replicon revealed critical genotype-3-specific polymorphism for drug resistance and viral fitness

  • Antiviral Res. 2019 Nov;171:104612. doi: 10.1016/j.antiviral.2019.104612.
Mingzhe Guo 1,  Jie Lu 2,  Tianyu Gan 3,  Xiaogang Xiang 2,  Yongfen Xu 4,  Qing Xie 2,  Jin Zhong 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; Shanghai Tech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Department of Infectious Disease, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3 CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 5 CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; Shanghai Tech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: jzhong@ips.ac.cn.
PMID: 31542377 DOI: 10.1016/j.antiviral.2019.104612
Abstract

Hepatitis C virus (HCV), a major causative agent of chronic hepatitis, is a positive-stranded RNA virus and has a high degree of genetic diversity due to its error-prone RNA-dependent RNA polymerase. Development of direct-acting Antiviral agents (DAAs) has greatly improved the therapeutic outcome of chronic hepatitis C patients. However, naturally existing resistance-associated variants (RAVs) or occurrence of resistance-associated substitutions (RASs) in the HCV genome may impose a challenge to the long-term success of the DAA-based therapies. Genotype-3 HCV is the most difficult genotype to treat by DAAs, but the underlying molecular mechanisms remain to be explored. Here we developed a novel genotype-3a subgenomic replicon PR87A7 by screening a HCV cDNA pool amplified from a patient serum RNA. PR87A7 replicon displayed strong resistance to anti-NS3 DAAs, mainly owing to a genotype-3-specific polymorphism 168Q in NS3. Introduction of NS3 168Q into a genotype-2a JFH1 strain rendered resistance to anti-NS3 DAAs while greatly diminished the viral replication, and yet this fitness defect can be rescued by additional genotype-3-specific polymorphism. In conclusion, we developed a novel genotype-3a subgenomic replicon by a functional screening approach, and revealed genotype-3-specfic amino acid residues that confer resistance to anti-NS3 DAAs while retaining viral fitness.

Keywords

Antiviral resistance; Direct-acting antiviral agents; Genotype-3; Hepatitis C virus; Replicon.

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