Effects of Interferon-α/β on HBV Replication Determined by Viral Load

Interferons alpha and beta (IFN-alpha/beta) are type I interferons produced by the host to control microbial infections. However, the use of IFN-alpha to treat hepatitis B virus (HBV) patients generated sustained response to only a minority of patients. By using HBV transgenic mice as a model and by using hydrodynamic injection to introduce HBV DNA into the mouse liver, we studied the effect of IFN-alpha/beta on HBV in vivo. Interestingly, our results indicated that IFN-alpha/beta could have opposite effects on HBV: they suppressed HBV replication when viral load was high and enhanced HBV replication when viral load was low. IFN-alpha/beta apparently suppressed HBV replication via transcriptional and post-transcriptional regulations. In contrast, IFN-alpha/beta enhanced viral replication by inducing the transcription factor HNF3 gamma and activating STAT3, which together stimulated HBV gene expression and replication. Further studies revealed an important role of IFN-alpha/beta in stimulating viral growth and prolonging viremia when viral load is low. This use of an innate immune response to enhance its replication and persistence may represent a novel strategy that HBV uses to enhance its growth and spread in the early stage of viral infection when the viral level is low.