Development of robust genotype 1a hepatitis C replicons harboring adaptive mutations for facilitating the antiviral drug discovery and study of virus replication
| Autor: | Pei-Shan Wu, Han-Shu Hu, Ren-Huang Wu, Hui-Mei Lin, Wan-Chun Chang, Jia-Ni Tian, Jyh-Haur Chern, Andrew Yueh |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genotype medicine.drug_class viruses Hepatitis C virus 030106 microbiology Adaptation Biological Drug Evaluation Preclinical Hepacivirus Biology Virus Replication medicine.disease_cause Antiviral Agents Cell Line 03 medical and health sciences Adaptive mutation Virology medicine Humans Replicon NS3 Mutation biochemical phenomena metabolism and nutrition Viral replication Hepatocytes Antiviral drug |
| Zdroj: | Journal of Virological Methods. 259:10-17 |
| ISSN: | 0166-0934 |
| Popis: | The hepatitis C virus (HCV) subgenomic replicon is a valuable tool for studying virus replication and HCV drug development. Despite the fact that HCV genotype 1a (HCV1a) is the most prevalent genotype in the United States, few HCV1a reporter replicon constructs have been reported, and their replication capacities are not as efficient as those of HCV1b or 2a, especially in transient expression. In this study, we selected efficient HCV1a replicons and characterized the novel adaptive mutations derived from stable HCV1a (strain H77) replicon cells after G418 selection. These novel adaptive mutations were scored in NS3 (A1065V, C1073S, N1227D, D1431Y, and E1556G), NS4A (I1694T and E1709V), and NS4B (G1871C). The D1431Y mutation alone or combinations of other adaptive mutations introduced into the parental HCV1a replicon construct was observed to differentially enhance either transient or stable expression of replicon. In particular, two replicon mutants VDYG (A1065V, N1227D, D1431Y, and E1556G within NS3) and VDYGRG, VDYG with two additional adaptive mutations (NS4A-K1691R and NS4B-E1726G), displayed robust replication and exhibited no impairment in the susceptibility of replicon activity to various known HCV inhibitors. |
| Databáze: | OpenAIRE |
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