Work

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

Year: 2025

Type: article

Abstract: ABSTRACT Chronic hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. Although humans produce 12 subtypes of interferon-alpha (IFN-α), IFN-α2a has been the only commonly used treatment against HDV. Previously, we characterized eight HDV genotype isolates with varying replication kinetics. Herein, we systematically investigated the antiviral efficacy of IFN-α2a and other IFN-α subtypes against HDV genotypes 1–8 during de novo infection, cell mitosis, and in quiescent cells. Our findings revealed that IFN-α2a 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-α2a treatment and the IFN-containing cytokine cocktail collected from peripheral blood mononuclear cells stimulated with TLR7/8 agonist. Mechanistically, both ADAR1 p110 and p150 promote L-HDAg production and inhibit HDV replication. ADAR1 p150, rather than p110, enhances the anti-HDV efficacy of IFN-α during de novo infection and cell mitosis, but not in resting cells. Moreover, different subtypes of IFN-α exhibit varying anti-HDV activities in both de novo infection and cell mitosis, due to their disparity in activating interferon responses. Among these, IFN-α2a, IFN-α10, and IFN-α14 exhibit the strongest anti-HDV activity and synergize with bulevirtide in suppressing HDV replication. In conclusion, the anti-HDV efficacy of IFN-α depends on multiple factors, including HDV genotypes, ADAR1 p150 level, IFN-α subtypes, and HDV’s different survival strategies. These findings provide valuable implications for the development and optimization of IFN-based therapies. IMPORTANCE 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.

Source: Journal of Virology

DOI: 10.1128/jvi.01280-25