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Assembly and infection efficacy of hepatitis B virus surface protein exchanges in eight hepatitis D virus genotype isolates
J Hepatol. 2021 Apr 9;S0168-8278(21)00229-4. doi: 10.1016/j.jhep.2021.03.025.Online ahead of print.
Wenshi Wang1, Florian A Lempp2, Franziska Schlund3, Lisa Walter3, Charlotte Decker3, Zhenfeng Zhang3, Yi Ni2, Stephan Urban4
1Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: Wenshi.Wang@med.uni-heidelberg.de.
2Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Centre for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany.
3Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
4Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Centre for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. Electronic address: Stephan.Urban@med.uni-heidelberg.de.
Background & aims: Chronic hepatitis D virus (HDV) infections cause the most severe form of viral hepatitis. HDV requires hepatitis B virus (HBV) envelope proteins for hepatocyte entry, particle assembly and release. Eight HDV and eight HBV genotypes are presently distinguished. However, comparing data of replication competence of HDV isolated from different genotypes lacks. Furthermore, it is unknown to what extent combination with different HBV envelopes affect virion assembly and infectivity.
Methods: We subcloned cDNAs of all HDV and HBV genotypes and systematically studied HDV replication, assembly and infectivity using Northern Blot, Western Blot, RT-qPCR, in-cell ELISA.
Results: The eight HDV cDNA clones initiated HDV replication with noticeable differences regarding replication efficacy. The eight HBV-HBsAg-encoding constructs all supported secretion of subviral particles, however variations in envelope protein stoichiometry and secretion efficacy were observed. Co-transfection of all HDV/HBV combinations supported particle assembly, however, the respective pseudo-typed HDVs differed with respect to assembly kinetics. The most productive combinations did not correlate to the natural geographic distribution arguing against an evolutionary adaptation of HDV ribonucleoprotein complex to HBV envelopes. All HDVs elicited robust and comparable innate immune responses. HBV envelope-dependent differences in the activity of the EMA approved entry inhibitor Hepcludex were observed, however efficient inhibition could be achieved at therapeutically applied doses. Lonafarnib, the assembly inhibitor in development also showed pan-genotypic activity.
Conclusions: HDVs from different genotypes replicate with variable efficacies. Variations of HDV genomes and HBV-envelopes both are major determinants for HDV egress and entry efficacy and consequently assembly inhibition by Lonafarnib or entry inhibition by Hepcludex. These differences possibly influence HDV pathogenicity, immune responses and the efficacy of novel drug regimens.
Lay summary: Hepatitis D virus (HDV) needs hepatitis B virus (HBV) to provide envelope protein for virus assembly and de novo entry. Eight HDV and eight HBV genotypes are presently distinguished. In this study, we comprehensively investigated replication competence, envelopment preference and kinetics of virion secretion of all HDV genotypes. We found that different genotypes of HDV replicate with variable efficacies. Genotypic variations in HDV and HBV-envelopes are major determinants for HDV assembly, de novo entry and consequently the efficacy of novel antivirals.