title: Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection.
abstract: OBJECTIVE
  Clinical studies have shown that hepatitis delta virus (HDV) infection can persist for years and intrahepatic latency of the large delta antigen (HDAg) has been detected following liver transplantation. However, large HDAg arising via RNA-editing is associated with increasing amounts of non-infectious HDV quasi-species. This study investigated whether HDV could persist intrahepatically in the absence of HBV in vivo and whether infectious HDV could subsequently be released following HBV super-infection.
  
  
  METHODS
  Humanized mice were infected with HDV particles lacking HBV. To test for rescue of latent HDV infection 3 and 6 weeks HDV mono-infected mice were super-infected with HBV. Viral loads and cell toxicity were determined by qRT-PCR and immunohistochemistry.
  
  
  RESULTS
  The presence of HDAg-positive human hepatocytes determined after 2, 3, and 6 weeks of HDV inoculation demonstrated establishment and maintenance of intrahepatic HDV mono-infection. Although intrahepatic amounts of large HDAg and edited HDV RNA forms increased over time in HDV mono-infected livers, HBV super-infection led to prompt viremia development (up to 10(8) HDV RNA and 10(7) HBV-DNA copies/ml) even after 6 weeks of latent mono-infection. Concurrently, the number of HDAg-positive human hepatocytes increased, demonstrating intrahepatic HDV spreading. The infectivity of the rescued HDV virions was verified by serial passage in naive chimeric mice.
  
  
  CONCLUSIONS
  HDV mono-infection can persist intrahepatically for at least 6 weeks before being rescued by HBV. Conversion of a latent HDV infection to a productive HBV/HDV co-infection may contribute to HDV persistence even in patients with low HBV replication and in the setting of liver transplantation.
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Giersch
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Helbig
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Allweiss
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lida V
authors.initials: LV
authors.lastname: Mancke
authors.affiliation: I. Department of 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: Institute of Microbiology, Virology and Hygiene, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Polywka
authors.affiliation: Department for General, Visceral, Thoracic, and Vascular Surgery University Hospital Bonn, Germany.
authors.forename: Jörg M
authors.initials: JM
authors.lastname: Pollok
authors.affiliation: IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: John
authors.initials: J
authors.lastname: Taylor
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany. Electronic address: m.dandri@uke.de.
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Microbiology, Virology and Hygiene, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Lütgehetmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D060085:Coinfection / Q000821:virology*; D006509:Hepatitis B / Q000821:virology*; D006515:Hepatitis B virus / Q000502:physiology; D003699:Hepatitis D / Q000821:virology*; D003698:Hepatitis Delta Virus / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D014779:Virus Replication
keywords: HBV; HBV core antigen; HBV super-infection; HBV surface antigen; HBcAg; HBsAg; HDAg; HDV; HDV mono-infection; Human liver chimeric mice; Liver transplantation; USB; cccDNA; covalently closed circular DNA; hepatitis B virus; hepatitis delta antigen; hepatitis delta virus; uPA/SCID beige mice