Strain-specific responsiveness of hepatitis D virus to interferon treatment

Background & Aims: Pegylated interferon alpha (pegIFNa) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive and only a minority of people respond to pegIFNa therapy. Herein, we aimed to assess the responsiveness of three different cloned HDV strains to pegIFNa. We used a previously cloned HDV genotype 1 strain (dubbed HDV-1a) that appeared insensitive to interferon-a in vitro, a new HDV strain (HDV-1p) we isolated from an individual achieving later sustained response to IFNa therapy, and one phylogenetically distant genotype 3 strain (HDV-3).Methods: PegIFNa was administered to human liver chimeric mice infected with HBV and the different HDV strains or to HBV/ HDV infected human hepatocytes isolated from chimeric mice. Virological parameters and host responses were analysed by qPCR, sequencing, immunoblotting, RNA in situ hybridisation and immunofluorescence staining.Results: PegIFNa treatment efficiently reduced HDV RNA viraemia (-2-log) and intrahepatic HDV markers both in mice infected with HBV/HDV-1p and HBV/HDV-3. In contrast, HDV parameters remained unaffected by pegIFNa treatment both in mice (up to 9 weeks) and in isolated cells infected with HBV/HDV-1a. Notably, HBV viraemia was efficiently lowered (-2-log) and human interferon-stimulated genes similarly induced in all three HBV/HDV-infected mouse groups receiving pegIFNa. Genome sequencing revealed highly conserved ribozyme and L-hepatitis D antigen post-translational modification sites among all three isolates.Conclusions: Our comparative study indicates the ability of pegIFNa to lower HDV loads in stably infected human hepatocytes in vivo and the existence of complex virus-specific determinants of IFNa responsiveness.Impact and implications: Understanding factors counteracting HDV infections is paramount to develop curative therapies. We compared the responsiveness of three different cloned HDV strains to pegylated interferon alpha in chronically infected mice. The different responsiveness of these HDV isolates to treatment highlights a previously underestimated heterogeneity among HDV strains. & COPY; 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).