A stable hepatitis D virus-producing cell line for host target and drug discovery

• Published in: Antiviral research 2023-01, Vol.209, p.105477, Article 105477
• Main Authors: Bach, Charlotte, Lucifora, Julie, Delphin, Marion, Heydmann, Laura, Heuschkel, Margaux J., Pons, Caroline, Goto, Kaku, Scheers, Els, Schuster, Catherine, Durantel, David, Pauwels, Frederik, Baumert, Thomas F., Verrier, Eloi R.
• Format: Article
• Language: English
• Subjects: Antiviral Agents - pharmacology; Cell culture model; Cell Line; Drug Discovery; Hepatitis B virus; Hepatitis D virus; Hepatitis Delta Virus - genetics; Life Sciences; Lonafarnib; Microbiology and Parasitology; Virology; Virus Replication; Virus-host interactions
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2022.105477

Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. It is caused by super-infection of hepatitis B virus (HBV)-infected hepatocytes with hepatitis D virus (HDV). While the recent conditional approval of bulevirtide for HDV treatment offers a new therapeutic modality in Europe, there is an unmet medical need to further improve therapy. A more detailed characterization of virus-host interactions is needed for the identification of novel therapeutic targets. Addressing this need, we engineered a new stably-transformed cell line, named HuH7-2C8D, producing high titer recombinant HDV and allowing the study of viral particles morphogenesis and infectivity. Using this culture system, where viral propagation by re-infection is limited, we observed an increased accumulation of edited version of the viral genomes within secreted HDV viral particles over time that is accompanied with a decrease in viral particle infectivity. We confirmed the interaction of HDV proteins with a previously described host factor in HuH7-2C8D cells and additionally showed that these cells are suitable for co-culture assays with other cell types such as macrophages. Finally, the use of HuH7-2C8D cells allowed to confirm the dual antiviral activity of farnesyl transferase inhibitors, including the clinical candidate lonafarnib, against HDV. In conclusion, we have established an easy-to-handle cell culture model to investigate HDV replication, morphogenesis, and host interactions. HuH7-2C8D cells are also suitable for high-throughput antiviral screening assays for the development of new therapeutic strategies.