Hepatitis B virus Infection inhibits responsiveness to interferon alpha treatment in human hepatocytes in vivo

Aims: The molecular mechanisms responsible for hepatitis B virus (HBV) weak responsiveness to IFN alpha treatment in the majority of HBV-chronically infected patients are poorly understood. Aim: to investigate whether HBV infection can restrain IFN-mediated induction of antiviral defence mechanisms in chronically infected human hepatocytes. Methods: After establishment of HBV-chronic infection in uPA/SCID mice reconstituted with primary human hepatocytes, both uninfected and HBV infected animals were treated with human IFN alpha. Viral changes, as well as induction of human specific interferon stimulated genes (ISGs) were determined by real-time PCR using human specific primers and by immunohistochemistry. Results: Significant reduction of HBV viremia (0.8log) and intrahepatic HBV RNA (3-fold) was determined in animals sacrificed 8 or 12hr after IFN injection, though viral suppression was abolished within 24hr post administration. IFN alpha treatment induced strong activation of ISGs, such as OAS-1, MxA, and MyD88 in uninfected human hepatocytes repopulating the livers of uPA/SCID control mice. Notably, RNA levels of the same ISGs did not significantly increase after IFN treatment in HBV infected mice harbouring hepatocytes isolated from the same human liver. Although HBV infection did not hinder IFN-mediated induction of HLA-I genes, we found that induction of a key player of the antigen processing pathway, TAP-1, was clearly restrained in HBV infected hepatocytes both at RNA and protein level. Conclusions: These results provide direct evidence that HBV infection can counteract activation of the IFN system in chronically infected human hepatocytes by blocking the induction of specific IFN target genes.

HBV - IFN alpha - uPA/SCID mice