Multimodal characterization of the responsiveness of eight hepatitis D virus genotype isolates to interferon-alpha treatment

Abstract

Chronic hepatitis delta virus (HDV) infection represents the most severe form of viral hepatitis. This study comprehensively evaluated the antiviral efficacy of interferon-alpha (IFN-α) subtypes across eight HDV genotypes during de novo infection, cell mitosis, or in quiescent cells. Herein, we found that IFN-α exhibits potent but varied efficiency against HDV 1–8 isolates upon de novo infection and cell mitosis. Conversely, HDVs in resting cells are resistant to IFN-α subtypes, regardless of the cellular ADAR1 levels. Among different subtypes, IFN-α2a, IFN-α10, and IFN-α14 exhibit the strongest anti-HDV activity and synergize with bulevirtide in suppressing HDV replication. These findings provide crucial insights into the optimization of IFN-based monotherapy and combinational therapy against chronic HDV infection.