2. Academic Validation
  3. Farnesoid X receptor alpha ligands inhibit HDV in vitro replication and virion infectivity

Farnesoid X receptor alpha ligands inhibit HDV in vitro replication and virion infectivity

  • Hepatol Commun. 2023 Apr 14;7(5):e0078. doi: 10.1097/HC9.0000000000000078.
Anne-Flore Legrand 1 2,  Julie Lucifora 2 3,  Benoît Lacombe 1,  Camille Ménard 1,  Maud Michelet 4,  Adrien Foca 1,  Pauline Abrial 1,  Anna Salvetti 2,  Michel Rivoire 5,  Vincent Lotteau 1,  David Durantel 2 3,  Patrice André 1 2,  Christophe Ramière 1 2 6
Affiliations

Affiliations

  • 1 CIRI, Centre International de Recherche en Infectiologie, Team VIRIMI, Univ Lyon, Inserm, Université Claude Bernard Lyon 1, CNRS, ENS de Lyon, Lyon, France.
  • 2 University of Lyon, Université Claude Bernard Lyon, Villeurbanne, France.
  • 3 CIRI, Centre ge International de Recherche en Infectiologie, Team HepVir, Univ Lyon, Inserm Université Claude Bernard Lyon 1, CNRS, ENS de Lyon, Lyon, France.
  • 4 INSERM U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS Centre Léon Bérard, Lyon, France.
  • 5 INSERM Centre Léon Bérard (CLB), Lyon, France.
  • 6 Virology Laboratory, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France.
PMID: 37058078 DOI: 10.1097/HC9.0000000000000078
Abstract

Background and aims: HDV, a satellite of HBV, is responsible for the most severe form of human viral hepatitis, for which curative therapy is still awaited. Both HBV and HDV use the hepatic transporter of bile acids (ie, Na+-taurocholate cotransporting polypeptide) to enter hepatocytes. We have previously shown that ligands of the farnesoid-X-receptor alpha (FXR), a master regulator of bile acids metabolism, inhibit HBV replication. Here we asked whether FXR ligands can also control HDV Infection.

Approach and results: In vitro HDV monoinfections or HDV/HBV coinfections and superinfections were performed in differentiated HepaRG cells (dHepaRG) and primary human hepatocytes. Following treatment with FXR ligands, HDV RNAs and antigens were analyzed by RT-qPCR, northern blot, immunofluorescence, and western blot. Virus secretion was studied by RNA quantification in supernatants, and the infectivity of secreted HDV particles was measured by reinfection of naive HuH7.5-Na+-taurocholate cotransporting polypeptide cells. In HDV/HBV superinfection models, a 10-day treatment with FXR ligand GW4064 decreased intracellular HDV RNAs by 60% and 40% in dHepaRG cells and primary human hepatocytes, respectively. Both HDV genomic and antigenomic RNAs were affected by treatment, which also reduced the amount of intracellular delta antigen. This Antiviral effect was also observed in HDV monoinfected dHepaRG cells, abolished by FXR loss of function, and reproduced with other FXR ligands. In HBV/HDV coinfected dHepaRG cells, HDV secretion was decreased by 60% and virion-specific infectivity by >95%.

Conclusions: FXR ligands both inhibit directly (ie, independently of anti-HBV activity) and indirectly (ie, dependently of anti-HBV activity) the replication, secretion, and infectivity of HDV. The overall anti-HDV activity was superior to that obtained with interferon-α, highlighting the therapeutic potential of FXR ligands in HDV-infected patients.

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