Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus
Résumé
In HBV-infected patients, therapies with nucleoside analogues or IFNalpha remain ineffective in eradicating the infection. Our aim was to re-analyze the anti-HBV activity of a large panel of IFNs and cytokines in vitro using non-transformed cultured hepatocytes infected with HBV, to identify new immune-therapeutic options. HepaRG cells and primary human hepatocytes were infected with HBV and, when infection was established, treated with various concentrations of different IFNs or inflammatory cytokines. Viral parameters were evaluated by quantifying HBV nucleic acids by qPCR and Southern Blot, and secreted HBV antigens were evaluated using ELISA. The cytokines tested were IFNbeta, IFNgamma, IFNlambda, TNFalpha, IL-6, IL-1beta, IL-18 as well as nucleos(t)ide analogues tenofovir and ribavirin. Cytokines and drugs, with the exception of IL-18 and ribavirin, exhibited a suppressive effect on HBV replication at least as strong as, but often stronger than, IFNalpha. The cytokine presenting the highest effect on HBV DNA was IL-1beta, which exerted its inhibition within picomolar range. Importantly, we noticed differential effects on other parameters (HBV RNA, HBeAg, HBsAg) between both IFNs and inflammatory cytokines, thus suggesting different mechanisms of action. The combination of IL-1beta and already used therapies, i.e. IFNalpha or tenofovir, demonstrated a stronger or similar anti-HBV activity. IL-1beta was found to have a very potent antiviral effect against HBV in vitro. HBV was previously shown to promptly inhibit IL-1beta production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1beta may help to further inhibit HBV replication in vivo