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

Heuschkel, Margaux J. ; Bach, Charlotte ; Meiss-Heydmann, Laura ; Gerges, Emma ; Felli, Emanuele ; Giannone, Fabio ; Pessaux, Patrick ; Schuster, Catherine ; Lucifora, Julie ; Baumert, Thomas F. ; Verrier, Eloi R.

Journal of hepatology, 2024-02, Vol.80 (2), p.220-231 [Periódico revisado por pares]

Netherlands: Elsevier B.V

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  • Título:
    JAK1 promotes HDV replication and is a potential target for antiviral therapy
  • Autor: Heuschkel, Margaux J. ; Bach, Charlotte ; Meiss-Heydmann, Laura ; Gerges, Emma ; Felli, Emanuele ; Giannone, Fabio ; Pessaux, Patrick ; Schuster, Catherine ; Lucifora, Julie ; Baumert, Thomas F. ; Verrier, Eloi R.
  • Assuntos: Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; antiviral treatment ; HDAg ; Hepatitis B virus ; Hepatitis D virus ; Hepatitis D, Chronic - drug therapy ; Hepatitis Delta Virus - physiology ; host factor ; Human health and pathology ; Humans ; Janus Kinase 1 ; kinase ; Life Sciences ; replication ; Virus Replication
  • É parte de: Journal of hepatology, 2024-02, Vol.80 (2), p.220-231
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
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  • Descrição: Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces 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 Janus kinase 1 (JAK1) – a key player in innate immunity – 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, which is 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. As no curative treatment is currently available, 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 player in 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 for the development of innovative therapeutic strategies to tackle this global health threat. [Display omitted] •JAK1 exhibits an unexpected proviral activity during HDV infection in various in vitro models, including primary human hepatocytes.•JAK1 proviral activity is independent of the MDA5-mediated innate immune response and the activation of STAT3.•JAK1 depletion is associated with inhibition of HDV replication via modulation of ERK1/2 and S-HDAg phosphorylation levels.•FDA-approved JAK1-specific inhibitors such as upadacitinib are efficient antivirals for the treatment of hepatitis D.
  • Editor: Netherlands: Elsevier B.V
  • Idioma: Inglês;Francês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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