Inhibition of hepatitis B virus production associated with high levels of intracellular viral DNA intermediates in iron-depleted HepG2.2.15 cells.
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.
Chouteau
P
P
INSERM U522, Régulations des Equilibres Fonctionnels du Foie Normal et Pathologique, H pital de Pontchaillou, Rennes, France.
Le Seyec
J
J
Saulier-Le Dréan
B
B
Cannie
I
I
Brissot
P
P
Lescoat
G
G
Guguen-Guillouzo
C
C
Gripon
P
P
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
D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral; D007501:Iron; D003676:Deferoxamine; D006918:Hydroxyurea