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Bockmann, J.H. ; Stadler, D. ; Xia, Y. ; Ko, C. ; Wettengel, J.M. ; Zur Wiesch, J.S.* ; Dandri, M.* ; Protzer, U.

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

J. Infect. Dis. 220, 567-577 (2019)

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Background. Type III interferons (IFNs) (lambda 1-3) activate similar signaling cascades as type I IFNs (alpha and beta) via different receptors. Since IFN-alpha and lymphotoxin-beta activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-beta and -lambda may also induce these antiviral effects in differentiated HBV-infected hepatocytes.Methods. After determining the biological activity of IFN-alpha 2,-beta 1, -lambda 1, and -lambda 2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV-infected primary human hepatocytes and HepaRG cells.Results. Type I and III IFNs reduced nuclear open-circle DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-beta and -lambda were at least as efficient as IFN-alpha. Differential DNA-denaturing polymerase chain reaction and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-alpha, -beta, and -lambda-treated liver cells indicating deamination. All IFNs induced apolipoprotein B messenger RNA-editing enzyme-catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours of treatment, but IFN-beta and -lambda induced longer-lasting expression of APOBEC deaminases in comparison to IFN-alpha.Conclusions. IFN-beta, IFN-lambda 1, and IFN-lambda 2 induce cccDNA deamination and degradation at least as efficiently as IFN-alpha, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.

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