title: Hepatitis delta virus infects the cells of hepadnavirus-induced hepatocellular carcinoma in woodchucks.
abstract: Hepatitis delta virus (HDV) is a natural subviral agent of human hepatitis B virus (HBV). HDV enhances liver damage during concomitant infection with HBV. The molecular pathogenesis of HDV infection remains poorly understood. To advance our understanding of the relationship between HDV infection and liver cancer, it was determined whether HDV could infect in vivo the cells of hepadnavirus-induced hepatocellular carcinoma (HCC). Woodchucks (Marmota monax) that were chronically infected with HBV-related woodchuck hepatitis virus (WHV) and already developed HCCs were used as an experimental model. The locations of HCCs within the livers were determined using ultrasound imaging followed by open surgery. One week after surgery the WHV carrier woodchucks were superinfected with WHV-enveloped HDV (wHDV). Six weeks later the animals were sacrificed and HDV replication in normal liver tissues and in center masses of HCCs was evidenced by Northern analysis, real-time polymerase chain reaction assay, and immunohistochemistry. Based on accumulation levels of HDV RNAs and numbers of infected cells, the efficiency of wHDV infection appears to be comparable in most HCCs and normal liver tissues.
  
  
  CONCLUSIONS
  Cells of WHV-induced HCCs are susceptible to HDV infection in vivo, and therefore express functional putative WHV receptors and support the steps of the attachment/entry governed by the hepadnavirus envelope proteins. Because others previously hypothesized that hepadnavirus-induced HCCs are resistant to reinfection with a hepadnavirus in vivo, our data suggest that if such a resistance exists it likely occurs via a block at the post-entry step. The demonstrated ability of HDV to infect already formed HCCs may facilitate development of novel strategies further dissecting the mechanism of liver pathogenesis associated with HDV infection.
authors.affiliation: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Freitas
authors.forename: Jessica
authors.initials: J
authors.lastname: Salisse
authors.forename: Celso
authors.initials: C
authors.lastname: Cunha
authors.forename: Ilia
authors.initials: I
authors.lastname: Toshkov
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
authors.forename: Severin O
authors.initials: SO
authors.lastname: Gudima
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000821:virology*; D060085:Coinfection / Q000821:virology; D004195:Disease Models, Animal; D015613:Hepadnaviridae / Q000235:genetics* / Q000378:metabolism; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics / Q000378:metabolism; D003698:Hepatitis Delta Virus / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D008392:Marmota; D012367:RNA, Viral / Q000032:analysis; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D012680:Sensitivity and Specificity; D014779:Virus Replication / Q000235:genetics*
chemical_list: D012367:RNA, Viral