title: Inhibition of hepatitis B virus production associated with high levels of intracellular viral DNA intermediates in iron-depleted HepG2.2.15 cells.
abstract: OBJECTIVE
  The effects of iron-depletion on hepatitis B virus (HBV) replication were examined in HepG2.2.15 cells.
  
  
  METHODS
  Proliferating cells were iron-depleted with desferrioxamine (DFO), at 20 or 100 microM for 48 h. Levels of viral mRNAs, cytoplasmic DNA replicative intermediates and virion production were examined. A comparative study was performed with hydroxyurea, a specific inhibitor of ribonucleotide reductase.
  
  
  RESULTS
  In desferrioxamine treated cells, virion production is dramatically decreased, while viral replicative intermediates accumulate in the cytoplasm. DFO, like hydroxyurea, blocks cell cycle progression in the G1/S transition or S phase with a corresponding 2-fold increase of viral mRNAs. As expected, hydroxyurea leads to a strong reduction of virion production associated with low levels of intracellular replicative intermediates.
  
  
  CONCLUSIONS
  These results strongly suggest that iron depletion affects the HBV life cycle indirectly through the cell cycle arrest and directly through the inhibition of the viral DNA secretion. They also indicate the need to re-evaluate with caution the iron depletion protocols on HBV infected patients since a decrease of viral markers in the serum following iron-depletion may not reflect a decrease of viral replicative forms, but on the contrary, could be associated with active viral DNA synthesis.
authors.affiliation: INSERM U522, Régulations des Equilibres Fonctionnels du Foie Normal et Pathologique, H pital de Pontchaillou, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Chouteau
authors.forename: J
authors.initials: J
authors.lastname: Le Seyec
authors.forename: B
authors.initials: B
authors.lastname: Saulier-Le Dréan
authors.forename: I
authors.initials: I
authors.lastname: Cannie
authors.forename: P
authors.initials: P
authors.lastname: Brissot
authors.forename: G
authors.initials: G
authors.lastname: Lescoat
authors.forename: C
authors.initials: C
authors.lastname: Guguen-Guillouzo
authors.forename: P
authors.initials: P
authors.lastname: Gripon
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004279:DNA, Viral / Q000032:analysis* / Q000096:biosynthesis; D003676:Deferoxamine / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007501:Iron / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral; D007501:Iron; D003676:Deferoxamine; D006918:Hydroxyurea