Lack of a role of the interferon-stimulated response element-like region in interferon α-induced suppression of hepatitis B virus in vitro

The antiviral effect of interferon-alpha (IFN alpha) on hepatitis B virus (HBV) is well documented in vitro and in vivo, but the mechanisms involved are elusive. Recently, an interferon-stimulated response like element (ISRE) competent for binding of interferon-stimulated gene Factor-3 gamma (p48) has been identified in the HBV enhancer I region. Mutation of this element was shown to abrogate IFN alpha -mediated reduction of HBV X-gene promoter-driven reporter gene expression. This suggested a role of the ISRE and of p48 in IFN alpha -induced antiviral activity against productive HBV infection. Here, we analyzed the antiviral effect of both IFNa and enhanced p48 expression on complete HBV genomes containing the wildtype or mutated ISRE. In human hepatoma cells transfected with both genomes, viral RNA and replicative intermediates were reduced by IFNa treatment to a similar degree. Enhanced p48 expression increased IFN alpha -induced suppression of HBV RNA significantly from 75 +/- 22.5% to 46 +/- 9.8%, but this was independent of the integrity of the ISRE-like region. These data imply that p48 neither mediates the antiviral activity of IFNa against HBV nor down-regulates enhancer I activity by binding directly to the HBV ISRE-like region, but rather argue for an indirect role of p48,