title: Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation.
abstract: OBJECTIVE
  Hepatitis E virus (HEV) is a major cause of acute hepatitis as well as chronic infection in immunocompromised individuals; however, in vivo infection models are limited. The aim of this study was to establish a small animal model to improve our understanding of HEV replication mechanisms and permit the development of effective therapeutics.
  
  
  METHODS
  UPA/SCID/beige mice repopulated with primary human hepatocytes were used for infection experiments with HEV genotype (GT) 1 and 3. Virological parameters were determined at the serological and intrahepatic level by real time PCR, immunohistochemistry and RNA in situ hybridization.
  
  
  RESULTS
  Establishment of HEV infection was achieved after intravenous injection of stool-derived virions and following co-housing with HEV-infected animals but not via inoculation of serum-derived HEV. GT 1 infection resulted in a rapid rise of viremia and high stable titres in serum, liver, bile and faeces of infected mice for more than 25 weeks. In contrast, viremia in GT 3 infected mice developed more slowly and displayed lower titres in all analysed tissues as compared to GT 1. HEV-infected human hepatocytes could be visualized using HEV ORF2 and ORF3 specific antibodies and HEV RNA in situ hybridization probes. Finally, six-week administration of ribavirin led to a strong reduction of viral replication in the serum and liver of GT 1 infected mice.
  
  
  CONCLUSIONS
  We established an efficient model of HEV infection to test the efficacy of antiviral agents and to exploit mechanisms of HEV replication and interaction with human hepatocytes in vivo.
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Allweiss
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Gass
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Giersch
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Groth
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kah
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gianna
authors.initials: G
authors.lastname: Rapp
authors.affiliation: Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schöbel
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Polywka
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Pischke
authors.affiliation: Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herker
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany.
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
authors.affiliation: Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: mluetgeh@uke.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Lütgehetmann
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016751:Hepatitis E / Q000188:drug therapy* / Q000821:virology; D016752:Hepatitis E virus / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000473:pathology / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D012367:RNA, Viral / Q000032:analysis*; D060888:Real-Time Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral
keywords: Chronic viral hepatitis; Hepatitis E Virus (HEV); Humanized mice; Preclinical drug testing; Ribavirin; uPA/SCID/beige