ABSTRACT
The
Hepatitis C virus (HCV), a member of the family
Flaviviridae, is a major cause of chronic liver disease.
Patients are currently treated with alpha interferon (IFN-α)
that is given alone or in combination with ribavirin. Unfortunately,
this treatment is ineffective in eliminating the virus in a large
proportion of individuals. IFN-induced antiviral activities have been
intensively studied in the HCV replicon system. It was found that both
IFN-α and IFN-γ inhibit HCV replicons, but the
underlying mechanisms have not yet been identified. Of note is that
nearly all of these studies were performed with the human hepatoma cell
line Huh-7. Here, we report that genotypes 1b and 2a replicons also
replicate in the human hepatoblastoma cell line HuH6. Similar to what
has been described for Huh-7 cells, we observed that efficient HCV
replication in HuH6 cells depends on the presence of cell
culture-adaptive mutations and the permissiveness of the host cell.
However, three major differences exist: in HuH6 cells, viral
replication is (i) independent from ongoing cell proliferation, (ii)
less sensitive to certain antiviral compounds, and (iii) highly
resistant to IFN-γ. The latter is not due to a general defect
in IFN signaling, as IFN-γ induces the nuclear translocation of
signal transducer and activator of transcription 1 (STAT1), the
enhanced transcription of several IFN-regulated genes, and the
inhibition of unrelated viruses such as influenza A virus and Semliki
Forest virus. Taken together, the results establish HuH6 replicon cells
as a valuable tool for IFN studies and for the evaluation of antiviral
compounds.
Approaches for the Development of Antiviral Compounds: The Case of Hepatitis C Virus
