title: HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes.
abstract: Hepatitis D virus (HDV) super-infection of Hepatitis B virus (HBV)-infected patients is the most aggressive form of viral hepatitis. HDV infection is not susceptible to direct anti-HBV drugs, and only suboptimal antiviral responses are obtained with interferon (IFN)-alpha-based therapy. To get insights on HDV replication and interplay with HBV in physiologically relevant hepatocytes, differentiated HepaRG (dHepaRG) cells, previously infected or not with HBV, were infected with HDV, and viral markers were extensively analyzed. Innate and IFN responses to HDV were monitored by measuring pro-inflammatory and interferon-stimulated gene (ISG) expression. Both mono- and super-infected dHepaRG cells supported a strong HDV intracellular replication, which was accompanied by a strong secretion of infectious HDV virions only in the super-infection setting and despite the low number of co-infected cells. Upon HDV super-infection, HBV replication markers including HBeAg, total HBV-DNA and pregenomic RNA were significantly decreased, confirming the interference of HDV on HBV. Yet, no decrease of circular covalently closed HBV DNA (cccDNA) and HBsAg levels was evidenced. At the peak of HDV-RNA accumulation and onset of interference on HBV replication, a strong type-I IFN response was observed, with interferon stimulated genes, RSAD2 (Viperin) and IFI78 (MxA) being highly induced. We established a cellular model to characterize in more detail the direct interference of HBV and HDV, and the indirect interplay between the two viruses via innate immune responses. This model will be instrumental to assess molecular and immunological mechanisms of this viral interference.
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France.
authors: Dulce
authors: D
authors: Alfaiate
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France. Electronic address: julie.lucifora@inserm.fr.
authors: Julie
authors: J
authors: Lucifora
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France.
authors: Natali
authors: N
authors: Abeywickrama-Samarakoon
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France.
authors: Maud
authors: M
authors: Michelet
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France.
authors: Barbara
authors: B
authors: Testoni
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France.
authors: Jean-Claude
authors: JC
authors: Cortay
authors: Institut National de Transfusion Sanguine, Laboratoire de Virologie Moléculaire, 75015 Paris, France.
authors: Camille
authors: C
authors: Sureau
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France; Laboratoire d'excellence (LabEx), DEVweCAN, 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France.
authors: Fabien
authors: F
authors: Zoulim
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; Université Paris 13/SPC, UFR SMBH, Laboratoire de Bactériologie, Virologie - Hygiène, GHU Paris Seine Saint Denis, Assistance Publique - Hôpitaux de Paris, Bobigny, France. Electronic address: paul.deny@inserm.fr.
authors: Paul
authors: P
authors: Dény
authors: INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France; Laboratoire d'excellence (LabEx), DEVweCAN, 69008 Lyon, France. Electronic address: david.durantel@inserm.fr.
authors: David
authors: D
authors: Durantel
mesh_terms: D002478:Cells, Cultured; D060085:Coinfection; D004261:DNA Replication; D004270:DNA, Circular; D006509:Hepatitis B / Q000821:virology; D006513:Hepatitis B e Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000502:physiology*; D003699:Hepatitis D / Q000821:virology; D003698:Hepatitis Delta Virus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D014762:Viral Interference; D014779:Virus Replication; D000090123:Viperin Protein
chemical_list: D004270:DNA, Circular; D006513:Hepatitis B e Antigens; D007370:Interferon Type I; D007372:Interferons; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D012367:RNA, Viral; C579071:MX1 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein
keywords: Hepatitis B virus; Hepatitis D virus; IFN response; Interferon stimulated genes; Viral interference