Establishment of authentic HCV replication systems for drug screening

  Although the interferon‐based therapeutics for chronic hepatitis C has improved remarkably over the decades, in some groups of patients the current therapeutic efficacy is far from satisfactory. Although new therapeutics is vigorously sought, the lack of appropriate cell culture systems and small animal models greatly hindered the progress of drug development. By introducing a selection marker into the HCV subgenomes, several successful replicon constructs were established. HCV replicons harboring adaptive mutations confer markedly increased efficiencies of replication. Furthermore, Huh‐7 cells carrying replicon that contained the whole genome were established but these cells were unable to secrete infectious viral particles. By use of SCID mice carrying a plasmogen activator transgene, an animal model carrying a chimeric human liver was established. These mice are permissive for HCV infection and the viral passages can be achieved successfully. However, the accessibility of this system is limited. By use of a molecular screening strategy, a hepatic factor, Sip‐L, is found to be capable of supporting HCV replication in an otherwise non‐permissive cell line. Potentially, this factor may be used to promote the infectivity and replication in other known permissive cell lines. An ex vivo assay using human liver biopsy slices has been established. This method can be used to test new anti‐HCV agents. In conclusion, although much progress has been made, culture cells permissive for highly efficient HCV infection are still lacking. An easily accessible small animal model is still in need. Much effort is still needed to establish an efficient and easily accessible authentic HCV replication system.