Abstract
Interferon-α (IFN-α) is used to treat chronic 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 remain 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 hepatocyte was generally similar across genotype A2, B5, C2 and D3, however, was significantly different among the infection models as the IC50 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 cccDNA 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. Conclusion: In the cell culture-based HBV infection models, the sensitivity of HBV to IFN-α in hepatocytes is determined more by the cell-intrinsic interferon response than by viral genotype, and improvement of the IFN response in HepG2-NTCP cells promotes the efficacy of IFN-α against HBV. This article is protected by copyright. All rights reserved.
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