Hepatitis delta virus inhibits alpha interferon signaling

Hepatitis delta virus (HDV) can cause severe acute and chronic liver disease in patients infected with hepatitis B virus. Interferon‐α (IFN‐α) is the only treatment reported to be effective in chronic hepatitis delta, albeit in a minority of patients. The molecular mechanisms underlying resistance to therapy are unclear. IFN‐α–induced activation of the Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) signaling cascade is essential for the induction of an antiviral state. Interference of HDV with the JAK‐STAT pathway could be responsible for the IFN‐α resistance in chronic hepatitis delta patients. We analyzed IFN‐α–induced signal transduction through the JAK‐STAT pathway in human hepatoma cells transfected with the complete HDV genome. The expression of IFN‐α–stimulated genes was investigated with reverse transcription real‐time polymerase chain reaction (PCR). STATs and JAKs activations were examined by immunofluorescence and immunoblot. The IFN‐α–stimulated genes coding for the antiviral proteins myxovirus resistance A, double‐stranded RNA (dsRNA)‐activated protein kinase and 2′,5′‐oligoadenylate synthetase were down‐regulated in HDV‐transfected hepatoma cells in response to IFN‐α treatment. HDV severely impaired the phosphorylation of both STAT1 and STAT2, thus preventing their accumulation in the nucleus. Furthermore, HDV blocked the IFN‐α–stimulated tyrosine phosphorylation of IFN receptor‐associated JAK kinase Tyk2, without affecting either the tyrosine phosphorylation of Jak1 or the expression of type I IFN receptor subunits. Conclusions: IFN‐α–induced intracellular signaling is impaired in HDV‐transfected human hepatoma cells. HDV subverts the effect of IFN‐α by blocking Tyk2 activation, thereby resulting in selective impairment of activation and translocation to the nucleus of STAT1 and STAT2. Interference of HDV with IFN‐α signaling could represent an important mechanism of viral persistence and treatment resistance. (HEPATOLOGY 2008.)