Abstract |
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. 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 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).
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Authors | Fang Shen, Yaming Li, Yang Wang, Vitina Sozzi, Peter A Revill, Jiangxia Liu, Lu Gao, Guang Yang, Mengji Lu, Kathrin Sutter, Ulf Dittmer, Jieliang Chen, Zhenghong Yuan |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 67
Issue 4
Pg. 1237-1252
(04 2018)
ISSN: 1527-3350 [Electronic] United States |
PMID | 29059468
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2017 by the American Association for the Study of Liver Diseases. |
Chemical References |
- Antiviral Agents
- DNA, Viral
- Interferon-alpha
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Topics |
- Antiviral Agents
(pharmacology)
- Blotting, Western
- Cell Culture Techniques
- DNA, Viral
- Genotype
- Hepatitis B
(drug therapy)
- Hepatitis B virus
(drug effects, genetics)
- Hepatocytes
(drug effects, virology)
- Humans
- Interferon-alpha
(pharmacology)
- Real-Time Polymerase Chain Reaction
- Virus Replication
(drug effects)
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