title: Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus.
abstract: In HBV-infected patients, therapies with nucleoside analogues or IFNα 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 type-I IFNs, IFNγ, type-III IFNs, TNFα, IL-6, IL-1β, 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, IFNα. The cytokine presenting the highest effect on HBV DNA was IL-1β, 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-1β and already used therapies, i.e. IFNα or tenofovir, demonstrated a stronger or similar anti-HBV activity. IL-1β was found to have a very potent antiviral effect against HBV in vitro. HBV was previously shown to promptly inhibit IL-1β production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1β may help to further inhibit HBV replication in vivo.
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Isorce
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Testoni
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
authors.forename: Maëlle
authors.initials: M
authors.lastname: Locatelli
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Fresquet
authors.affiliation: INSERM U1032, 69424 Lyon Cedex 03, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
authors.forename: Souphalone
authors.initials: S
authors.lastname: Luangsay
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France; Hospices Civils de Lyon (HCL), Liver Departement of Croix-Rousse Hospital, 69002 Lyon, France; Institut Universitaire de France (IUF), 75005 Paris, France. Electronic address: fabien.zoulim@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France. Electronic address: david.durantel@inserm.fr.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
mesh_terms: D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004279:DNA, Viral; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology*; D007372:Interferons / Q000494:pharmacology*; D012367:RNA, Viral; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000956:Antigens, Viral; D000998:Antiviral Agents; D016207:Cytokines; D004279:DNA, Viral; D007155:Immunologic Factors; D018836:Inflammation Mediators; D012367:RNA, Viral; D007372:Interferons
keywords: Antiviral effect; Hepatitis B virus; Immune-modulators; Innate immunity; Interferons; Pro-inflammatory cytokines