Abstract
The antiviral effect of interferon-alpha (IFNalpha) 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-3gamma (p48) has been identified in the HBV enhancer I region. Mutation of this element was shown to abrogate IFNalpha-mediated reduction of HBV X-gene promoter-driven reporter gene expression. This suggested a role of the ISRE and of p48 in IFNalpha-induced antiviral activity against productive HBV infection. Here, we analyzed the antiviral effect of both IFNalpha 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 IFNalpha treatment to a similar degree. Enhanced p48 expression increased IFNalpha-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 IFNalpha 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.
Highlights
To the endoplasmic reticulum and converted to mature virions for transport out of the cell or to the nucleus for the establishment of a pool of covalently closed circular DNA [2]
The STATs assemble with interferon stimulated gene factor 3␥ (p48) to form functional IFN-stimulated gene factor 3 (ISGF3), which translocates into the nucleus and binds to IFN-stimulated response elements (ISRE) located within the promoter region of IFN␣-inducible genes
Functional inactivation of the ISRE-like element that abrogated p48 binding in gel shift experiments abolished IFN␣-induced suppression of hepatitis B virus (HBV) enhancer I activity in reporter gene expression experiments performed with subgenomic HBV DNA fragments
Summary
To the endoplasmic reticulum and converted to mature virions for transport out of the cell or to the nucleus for the establishment of a pool of covalently closed circular DNA (cccDNA) [2]. Functional inactivation of the ISRE-like element that abrogated p48 binding in gel shift experiments abolished IFN␣-induced suppression of HBV enhancer I activity in reporter gene expression experiments performed with subgenomic HBV DNA fragments.
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