Lack of a Role of the Interferon-stimulated Response Element-like Region in Interferon α-induced Suppression of Hepatitis B Virus in Vitro

Abstract

The antiviral effect of interferon-α (IFNα) 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-3γ (p48) has been identified in the HBV enhancer I region. Mutation of this element was shown to abrogate IFNα-mediated reduction of HBV X-gene promoter-driven reporter gene expression. This suggested a role of the ISRE and of p48 in IFNα-induced antiviral activity against productive HBV infection. Here, we analyzed the antiviral effect of both IFNα and enhanced p48 expression on complete HBV genomes containing the wild-type or mutated ISRE. In human hepatoma cells transfected with both genomes, viral RNA and replicative intermediates were reduced by IFNα treatment to a similar degree. Enhanced p48 expression increased IFNα-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 IFNα 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.