Hepatitis B virus sensitivity to interferon‐α in... : Hepatology (original) (raw)

Original Articles: VIRAL HEPATITIS

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

Shen, Fang1,2,†; Li, Yaming1,†; Wang, Yang1; Sozzi, Vitina3; Revill, Peter A.3; Liu, Jiangxia1; Gao, Lu2; Yang, Guang2; Lu, Mengji4; Sutter, Kathrin4; Dittmer, Ulf4; Chen, Jieliang*,1; Yuan, Zhenghong*,1

1Key Laboratory of Medical Molecular Virology, School of Basic Medical SciencesShanghai Medical College of Fudan UniversityShanghaiChina

2Roche Innovation Center ShanghaiShanghaiChina

3Victorian Infectious Diseases Reference LaboratoryThe Royal Melbourne Hospital at the Peter Doherty Institute for Infection and ImmunityMelbourneAustralia

4Institute of Virology, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany

* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Zhenghong Yuan, Ph.D., M.D.
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
Room 1115
Zhidao Building
138 YiXueYuan Road
Shanghai 200032, China
E‐mail: [email protected]
Tel: +86‐21‐54237669;
or
Jieliang Chen, Ph.D., M.B.
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
Room 1115
Zhidao Building
138 YiXueYuan Road
Shanghai 200032, China
E‐mail: [email protected]
Tel: +86‐21‐54237669

†These authors contributed equally to this work.

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).