Different antiviral effects of IFN\u03b1 subtypes in a mouse model of HBV infection

Jingjiao Song,Jia Liu,Sheng Li,Sandra Francois,Yun Zhou,Ulf Dittmer,Mengji Lu,Kathrin Sutter,Dongliang Yang

doi:10.1038/s41598-017-00469-1

Jingjiao Song, Jia Liu + Show 7 more

Open Access

https://doi.org/10.1038/s41598-017-00469-1

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Abstract

Interferon alpha (IFNα) is commonly used for the treatment of chronic hepatitis B (CHB) patients. There are 13 different IFNα subtypes in humans, but only the subtype IFNα2 is used for clinical treatment. The antiviral activities of all other IFNα subtypes against HBV have not been studied. To obtain basic knowledge about the direct antiviral as well as the immunomodulatory effects of IFNα subtypes, we used the HBV hydrodynamic injection (HI) mouse model. Application of most IFNα subtype proteins inhibited HBV replication in vivo, with IFNα4 and IFNα5 being the most effective subtypes. Decreased viral loads after therapeutic application of IFNα4 and IFNα5 correlated with expanded effector cell populations of NK cells and T cells in both liver and spleen. Hydrodynamic injection of plasmids encoding for the effective IFNα subtypes (pIFNα) was even more potent against HBV than injecting IFNα proteins. The combination of pIFNα4 and pIFNα5 showed a synergistic antiviral effect on HBV replication, with a strong increase in NK cell and T cell activity. The results demonstrate distinct anti-HBV effects of different IFNα subtypes against HBV in the mouse model, which may be relevant for new therapeutic approaches.

Highlights

Hepatitis B virus (HBV) infection is one of the major threats to public health worldwide and more than 240 million people are currently infected
In the current work we aimed to investigate the antiviral effects of various mouse IFNα subtypes against HBV in vivo as well as their stimulatory effect on host innate and adaptive immune responses against HBV
We demonstrated that application of all IFNα subtypes except IFNα11 inhibited HBV replication in vivo, with IFNα4 and IFNα5 being the most effective subtypes

Summary

Introduction

Hepatitis B virus (HBV) infection is one of the major threats to public health worldwide and more than 240 million people are currently infected. Mice cannot be infected with HBV, whereas using the well-established HBV hydrodynamic injection (HI) mouse model, we are able to stably transfect mouse hepatocytes with an HBV expression plasmid This leads to the induction of a host immune response against HBV in the liver and mimicking HBV infection in vivo. Plasmid application resulted in long-term expression of IFNα in the liver Both experimental setups led to reduced HBV replication and antigen expression in the liver and IFNα4 and IFNα5 were the most effective subtypes which were able to suppress HBV replication. Both IFNα treatment regimens significantly improved NK and T cell effector functions correlating with accelerated viral clearance in the HBV HI mouse model

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