title: A rat model for hepatitis E virus.
abstract: Hepatitis E virus (HEV) is one of the prime causes of acute viral hepatitis, and chronic hepatitis E is increasingly recognized as an important problem in the transplant setting. Nevertheless, the fundamental understanding of the biology of HEV replication is limited and there are few therapeutic options. The development of such therapies is partially hindered by the lack of a robust and convenient animal model. We propose the infection of athymic nude rats with the rat HEV strain LA-B350 as such a model. A cDNA clone, pLA-B350, was constructed and the infectivity of its capped RNA transcripts was confirmed in vitro and in vivo Furthermore, a subgenomic replicon, pLA-B350/luc, was constructed and validated for in vitro antiviral studies. Interestingly, rat HEV proved to be less sensitive to the antiviral activity of α-interferon, ribavirin and mycophenolic acid than genotype 3 HEV (a strain that infects humans). As a proof-of-concept, part of the C-terminal polymerase sequence of pLA-B350/luc was swapped with its genotype 3 HEV counterpart: the resulting chimeric replicon replicated with comparable efficiency as the wild-type construct, confirming that LA-B350 strain is amenable to humanization (replacement of certain sequences or motifs by their counterparts from human HEV strains). Finally, ribavirin effectively inhibited LA-B350 replication in athymic nude rats, confirming the suitability of the rat model for antiviral studies.
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Yannick
authors.identifier: 0000-0001-6566-9408
authors.initials: Y
authors.lastname: Debing
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Niraj
authors.initials: N
authors.lastname: Mishra
authors.affiliation: Department of Imaging & Pathology, Translational Cell & Tissue Research, KU Leuven, Leuven 3000, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Verbeken
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Kaat
authors.initials: K
authors.lastname: Ramaekers
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Kai
authors.initials: K
authors.lastname: Dallmeier
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.identifier: 0000-0002-0033-7514
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002999:Clone Cells; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D016751:Hepatitis E / Q000473:pathology / Q000821:virology*; D016752:Hepatitis E virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000008:administration & dosage; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism; D011923:Rats, Nude; D012093:Replicon / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D017201:Virus Shedding / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D018076:DNA, Complementary; D012333:RNA, Messenger; D012367:RNA, Viral; D012324:RNA-Dependent RNA Polymerase
keywords: Animal model; Antiviral; Hepatitis E virus; LA-B350; Rat; Ribavirin