Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes

Background/Aims: Interferon-γ (IFN-γ) has been shown to abolish hepatitis B virus (HBV) gene expression and replication in HBV transgenic mice without destroying infected hepatocytes. We investigated the characteristics of IFN-γ induced non-cytolytic inhibition of viral replication in human HBV infection. Methods: We used an in vitro model where lymphocytes from 15 HBsAg positive patients were co-cultured with transfected hepatocytes supporting HBV replication. The effector and target cells were separated by a membrane, which allowed transfer of soluble factors only, to determine whether IFN-γ produced from antigen-specific CD4+ T cells or mitogen stimulated lymphocytes inhibits HBV replication. Results: IFN-γ produced following lymphocyte stimulation reduced cytoplasmic HBV DNA in the target cells. The degree of HBV DNA reduction correlated with the level of IFN-γ in the supernatants. Further investigations using naturally infected human hepatocytes confirmed that recombinant IFN-γ reduces HBV DNA and HBV RNA in these cells as well, in parallel with the induction of cellular interferon-responsive genes. This antiviral effect was without significant cytotoxicity and was more pronounced in hepatocytes from patients with low HBV replication. Conclusions: These results provide direct evidence that IFN-γ can inhibit both HBV transcription and replication in human hepatocytes without cell lysis.