Que faisons nous ?
Global Challenges
Hepato(cyto)tropic viruses through either acute or chronic infections can cause liver damages, leading to liver failure or end-stage liver diseases (e.g. cirrhosis, HCC). The study of these viruses’ interplay with liver cells/ pathways/ factors is instrumental for the identification of novel targets and the subsequent development of antiviral strategies leading to viral clearance and thereby liver protection.
Summary of main achievements (2019 - 2024)
Duringt the last five years, we conducted basic and translational research projects with the objective to gain relevant knowledge on HBV (+/-) HDV replication strategies and their interactions with host-factors/pathways in liver cells and identify/get knowledge on novel targets for the R&D of antiviral agents targeting the viruses or the host. The first axis of our research program was dedicated to the study of nuclear functions of the HBV core protein (HBc). We uncovered HBc nuclear protein-interactome, including several RNA-binding proteins that we found crucial for HBV replication (PLoS Pathog 2020, Front Microbiol 2024). Since HBc and RBP functions are modulated by phosphorylation, we also focused on kinases and identified DIRK1A as one being important for HBV replication (PLoS One 2024) and a possible target for antiviral molecules development (PCT/EP2018/076346). Interestingly, we demonstrated that HBc, coming from entering virions, is very early associated to HBV episome (JHEP Rep. 2021) to modulate HBV RNA biogenesis, and that these functions can be targeted by HBc inhibitors (called CAMs) (unpublished data). The second axis of our research program was dedicated to the study of the interplay between HBV/HDV and the liver cells responses. Using our consolidated study models (J Hepatol. 2020 and Cells. 2020), we showed that HBV can modulate innate cells functions, including liver macrophages (J Hepatol. 2019 and Viruses. 2021) to prevent the production of antiviral proinflammatory cytokines. We investigated the mechanism of negative interference between HBV and HDV, unravelling innate immune driven and viral protein specific direct mechanisms (J Hepatol. 2023). The third axis of our research program was dedicated to the development of new host targeting agents. We demonstrated (and got insights on underlaying molecular mechanisms) that TLR1/2 agonists were very active against HBV (Sci Rep. 2018, Antiviral Res. 2022) and HDV, the latter being extremely sensitive to NF-kB inducers in general (JHEP Rep. 2021). Additionally, we showed that, TLR1/2 agonists could be incorporated in PLA nanoparticles to obtain novel vaccinal platforms (Antiviral Res. 2023) and their therapeutic efficacy was investigated against HBV in preclinical animal models (unp. data). With the perspective of combination therapies, we also found that Farnesoid X Receptor’s agonists have strong antiviral effects on HBV/HDV (Hepatol Commun. 2023) and can synergize Peg-IFNa (unp. data), thereby mechanistically explaining interesting clinical data on HBV (unp. data). Very recently we demonstrated that FXR agonists are also active against HEV (JHEP Rep. 2025), opening new avenues toward the development of broad acting antiviral agents.
Research program
In the next years, we will progressively extend the scope of our work from classical hepatotropic viruses (HBV, HDV, HEV; that will remain the backbone) to more exotic hepatotropic viruses (YFV, CCHFV, RVFV…). To this end, we established a novel cell culture model, with primary human hepatocytes properties (JHEP Rep. 2025), sustaining infection with all the hepatotropic viruses tested so far (JHEP Rep. 2025+ unp. data) and we are currently setting mouse models (liver humanized + immune-competent). We will enhance our effort in basic research on liver cells/viruses interaction & the R&D of broadly acting antivirals. Our research program is divided in 4 interconnected axes. We focus on the interplay between hepatotropic viruses with liver-cell metabolism, host factors, and innate responses. We recently added a new area of research focusing on pandemic preparedness concepts, which will globally encompasses/structures our efforts.
Our research is supported by the ANRS