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J Infect Dis. 2019 Mar 29. pii: jiz143. doi: 10.1093/infdis/jiz143. [Epub ahead of print]

Comparative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepatocytes.

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Institute of Virology, Technische Universität München / Helmholtz Zentrum München, Munich, Germany.
I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center, Hamburg-Eppendorf; Hamburg, Germany.
German Center for Infection Research (DZIF), Munich and Hamburg partner sites, Germany.
State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.



Type III interferons (λ1-3) activate similar signaling cascades as type I interferons (α and β) via different receptors. Since interferon (IFN)-α and lymphotoxin-β activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-β and -λ may also induce these antiviral effects in differentiated, HBV infected hepatocytes.


After determining the biological activity of IFN-α2, -β1, -λ1 and -λ2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV infected primary human hepatocytes and HepaRG cells.


Type I and III IFNs reduced nuclear open-circle and covalently closed circular (ccc)DNA levels in HBV infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing PCR and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-α, -β and -λ treated liver cells indicating deamination. All IFNs induced APOBEC deaminases 3A and 3G within 24h of treatment, but IFN-β and -λ induced longer-lasting expression of APOBEC deaminases in comparison to IFN-α.


IFN-β, IFN- λ1 and IFN-λ2 induce cccDNA deamination and degradation at least as efficiently as IFN-α, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.


HBV; HepaRG cells; interferon-beta; interferon-lambda; primary human hepatocytes


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