Inhibition of Hepatitis Delta Virus by inducers of the NFκB pathway ; Inhibition du Virus de l’Hépatite Delta par des inducteurs de la voie NFκB

Super-infection by Hepatitis Delta Virus (HDV) of chronically Hepatitis B Virus (HBV) infected patients leads to the most aggressive forms of chronic viral hepatitis, with a faster progression towards fibrosis/cirrhosis and an increased risk of liver failure and hepatocellular carcinoma. Around 15-20 millions of people are co-infected with both viruses, which ranks this co-infection as one of the most prevalent and clinically challenging of the world. HDV infection is not susceptible to available direct anti-HBV. The only therapeutic option for HBV/HDV co-infected patients is the pegylated-interferon-α, a drug which has many side effects and suboptimal responses. Few molecules that target HDV are currently in development but none of them is affecting the replicative step of this virus. There is an urgent need to develop efficient treatment strategies for patients. An infection produced many cytokines. Different studies showed an activation of the interferon pathway during HDV infection in vitro and in vivo. Nevertheless, there is no current data available concerning an activation of the Nuclear factor κ B » (NFκB) pathway by HDV, and more than that our laboratory has suggested a lack of activation. Our purpose was to test the effect on HDV of various immunomodulatory drugs activating this pathway. After screening of various inducers of the canonical and non-canonical NFκB pathways we identified an agonist of the “toll like” receptor 1/2 (Pam3CSK4) and an agonist of the lymphotoxin β receptor (BS1) decreasing the HDV RNA and proteins. More extensive studies have shown a dose-dependent and stable anti-HDV effect despite an increase of the number of viral particles used to infect cells. Rebound experiments have shown a persistent antiviral effect and an alteration of the HDV particles infectivity. Its suggests an irreversible effect on HDV replication and transcription template. Transcriptomic analysis on HBV/HDV infected and treated with Pam3CSK4 and BS1 cells has confirmed the induction of the NFκB pathway and ...