Single-cell analysis of mature hepatocytes reveals an IRF1-driven restriction of HDV infection

We performed single-cell RNA sequencing of control and HDV-inoculated stem cell-derived hepatocytes, and characterised them in terms of hepatic differentiation, viral abundance and response to infection. We identified IRF1 as a constitutive cellular factor restricting HDV infection in mature hepatocytes, particularly targeting HDV in the cytoplasm. This work improves our understanding of mature cell culture models for HDV, needed to decipher its host-pathogens interactions. Identification of antiviral effector genes opens the way to the development of new host targeted antiviral strategies, particularly for targeting cell division-mediated spread that is not inhibited by currently used entry inhibitors (Hepcludex).