Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells.
OBJECTIVE
Chronic infection with hepatitis C virus (HCV) is often associated with elevated hepatic iron levels. Excess iron is known to promote oxidative stress and exacerbate liver disease. Nevertheless, biochemical studies in subgenomic HCV replicon systems showed that iron can also suppress the expression of viral RNA and proteins by inhibiting the enzymatic activity of the RNA polymerase NS5B. To explore the physiological relevance of this response, we evaluated the effects of iron during infection of permissive Huh7.5.1 hepatoma cells with HCV.


METHODS
We utilized Fe-SIH (iron complexed with salicylaldehyde isonicotinoyl hydrazone), a cell permeable and highly efficient iron donor.


RESULTS
Treatments of infected cells with Fe-SIH drastically reduced the expression of viral proteins (core and NS3) and RNA, in a dose-dependent manner. The inhibition was dramatic when Fe-SIH was administered simultaneously with the HCV inoculum or early afterwards, while pre-treatment of cells with Fe-SIH before infection failed to elicit antiviral responses. Iron chelation with SIH did not significantly alter the expression of viral proteins.


CONCLUSIONS
Our data establish a critical role of hepatic iron concentration on the progression of HCV infection, and are consistent with iron-mediated inactivation of NS5B.
Fillebeen
Carine
C
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2.
Pantopoulos
Kostas
K
D000447:Aldehydes / Q000008:administration & dosage; D000998:Antiviral Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage; D007501:Iron / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000447:Aldehydes; D000998:Antiviral Agents; D006835:Hydrazones; C413684:salicylaldehyde isonicotinoyl hydrazone; D007501:Iron