JAK1 promotes HDV replication and is a potential target for antiviral therapy

Liver chronic co-infection with hepatitis B and D viruses (HBV and HDV) is the most aggressive form of chronic viral hepatitis. To date, no treatment allows efficient viral clearance, and a better characterization of virus-host interactions is required to develop new therapeutic strategies.Using loss-of-function strategies, we validated the unexpected proviral activity of the innate immune-related Janus kinase 1 (JAK1) in the HDV life cycle and determined its mechanism of action on HDV through various functional analyses including co-immunoprecipitation assays.We confirmed the key role of JAK1 kinase activity in HDV infection. Moreover, our results suggest that JAK1 inhibition is associated with a modulation of ERK1/2 activation and S-HDAg phosphorylation, crucial for viral replication. Finally, we showed that FDA-approved JAK1-specific inhibitors are efficient antivirals in relevant in vitro models including primary human hepatocytes.Taken together, we uncovered JAK1 as a key host factor for HDV replication and a potential target for new antiviral treatment.Chronic hepatitis D is the most aggressive form of chronic viral hepatitis with no curative treatment. New therapeutic strategies based on host targeting agents are urgently needed. Here, using loss-of-function strategies, we uncover an unexpected interaction between JAK1, a major actor of the innate antiviral response, and HDV infection. We demonstrated that JAK1 kinase activity is crucial for both the phosphorylation of the delta antigen and the replication of the virus. By demonstrating the antiviral potential of several FDA-approved JAK1 inhibitors, our results could pave the way to the development of innovative therapeutic strategies to tackle this global health threat.