Comparative analysis of gene expression in HDV-infected dHepaRG cells upon treatment with IFN-α-2a or IFN-λ1

Viral cure is rarely achieved in infected patients. Interferon-alpha (IFN-α)-based therapies show suboptimal efficacy and low rates of sustained response, as reflected by their limited effect on HDV replication in vitro.

Here, we show that HDV infection induces cellular resistance to IFN-α, marked by impaired STAT1 phosphorylation and reduced expression of interferon-stimulated genes (ISGs) in hepatocyte-like cells. This refractoriness depends on virus-induced innate immune activation, highlighting the role of HDV-induced ISG expression in regulating IFN signalling. We identify USP18 as a key mediator of IFN-α resistance in infected cells.