Hepatitis B virus sensitivity to interferon‐α in hepatocytes is more associated with cellular interferon response than with viral genotype

Interferon-α (IFN-α) is used to treat chronic hepatitis B virus (HBV) infection, but only 20%-40% of patients respond well. Clinical observations have suggested that HBV genotype is associated with the response to IFN therapy; however, its role in viral responsiveness to IFN in HBV-infected hepatocytes remains unclear. Here, we produced infectious virions of HBV genotypes A to D to infect three well-recognized cell-culture-based HBV infection systems, including primary human hepatocytes (PHH), differentiated HepaRG (dHepaRG), and HepG2-NTCP cells to quantitatively compare the antiviral effect of IFN-α on HBV across genotypes and cell models. The efficacy of IFN-α against HBV in hepatocytes was generally similar across genotypes A2, B5, C2, and D3; however, it was significantly different among the infection models given that the half maximal inhibitory concentration value of IFN-α for inhibition of viral DNA replication in PHH (<20 U/mL) and dHepaRG cells were much lower than that in HepG2-NTCP cells (>500 U/mL). Notably, even in PHH, IFN-α did not reduce HBV covalently closed circular DNA at the concentrations for which viral antigens and DNA replication intermediates were strongly reduced. The three cell-culture models exhibited differential cellular response to IFN-α. The genes reported to be associated with responsiveness to IFN-α in patients were robustly induced in PHH while weakly induced in HepG2-NTCP cells upon IFN-α treatment. Reduction or promotion of IFN response in PHH or HepG2-NTCP cells significantly attenuated or improved the inhibitory capacity of IFN-α on HBV replication, respectively.In the cell-culture-based HBV infection models, the sensitivity of HBV to IFN-α in hepatocytes is determined more by the cell-intrinsic IFN response than by viral genotype, and improvement of the IFN response in HepG2-NTCP cells promotes the efficacy of IFN-α against HBV. (Hepatology 2018;67:1237-1252).