Fillebeen, C. et al. Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J. Hepatol. 47, 12-22

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Que., Canada H3T 1E2.
Journal of Hepatology (Impact Factor: 11.34). 07/2007; 47(1):12-22. DOI: 10.1016/j.jhep.2007.01.035
Source: PubMed


Infection with hepatitis C virus (HCV) is associated with alterations in body iron homeostasis by poorly defined mechanisms. To seek for molecular links, we employed an established cell culture model for viral replication, and assessed how the expression of an HCV subgenomic replicon affects iron metabolism in host Huh7 hepatoma cells.
The expression of iron metabolism genes and parameters defining the cellular iron status were analyzed and compared between parent and replicon Huh7 cells.
By using the IronChip microarray platform, we observed replicon-induced changes in expression profiles of iron metabolism genes. Notably, ceruloplasmin mRNA and protein expression were decreased in replicon cells. In addition, transferrin receptor 1 (TfR1) was also downregulated, while ferroportin levels were elevated, resulting in reduced iron uptake and increased iron release capacity of replicon cells. These responses were associated with an iron-deficient phenotype, manifested in decreased levels of the "labile iron pool" and concomitant induction of IRE-binding activity and IRP2 expression. Furthermore, hemin-treated replicon cells exhibited a defect in retaining iron. The clearance of the replicon by prolonged treatment with interferon-alpha only partially reversed the iron-deficient phenotype but almost completely restored the capacity of cured cells to retain iron.
We propose that Huh7 cells undergo genetic reprogramming to permit subgenomic viral replication that results in reduction of intracellular iron levels. This response may provide a mechanism to bypass iron-mediated inactivation of the viral RNA polymerase NS5B.

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    • "In conclusion, our findings provide evidence that HCV infection modulates iron metabolism and promotes iron deficiency in host hepatic cells. Similar responses were elicited by subgenomic HCV replicons; nevertheless, in this setting, iron deficiency was also associated with Fpn induction [7]. Conceivably, Fpn expression may be regulated by HCV structural proteins. "
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    • "Surprisingly, Hemin did not potentiate the anti-HCV activity of the most potent derivative (AJ-004). In line with previous findings [39]–[41], we showed that Hemin itself was able to inhibit the HCVcc replication. It is thus possible that the role of iron in the anti-HCV activity of ART and its derivatives may vary with the chemical structure of the compound. "
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    • "The topic is intriguing, and the role of Cu needs to be better explained, not only because Cu and oxLDL evaluations may have a deep diagnostic and prognostic impact, but also because a deep comprehension of their involvement in HCV-related disease could open the way to new antiviral approaches. Altered Cu homeostasis is associated with a reduction of ceruloplasmin [90] [91] [92]. This protein is important for both the trafficking of copper, binding 95% of circulating copper [70], and Fe, because, at hepatic level, it is the main ferroxidase enzyme, which is crucial for a proper Fe transport [93]. "
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