Editorial

Increased iron in HCV infection: Collateral damageor antiviral defense?

Sebastian Mueller*

Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University ofHeidelberg, Zeppelinstraße 11 – 33 69121 Heidelberg, Germany

See Article, pages 995–999

Despite two decades of research in antiviral therapy, we still havenot overcome a roughly 50% failure rate in the treatment ofpatients infected with the hepatitis C virus (HCV). Understandingthe interactions between host and virus seems to be a prerequi-site for any new therapeutic approach. Multiple axes of interac-tion have been suggested: cytokines, alterations of intracellularsignaling and metabolism e.g. of fatty acids. An imbalanced ironhomeostasis is another one: pathological iron deposits have beenobserved in about 50% of patients with chronic HCV infection.Increased hepatic iron stores are not a mere innocent bystander,but an important independent risk factor for the development ofhepatocellular cancer (HCC) in HCV-infected patients [1]. In addi-tion, we have learnt from hereditary hemochromatosis that ironoverload is one of the most profibrogenic and carcinogenic fac-tors increasing the risk of HCC by approximately 200-fold [2].The combination of free iron and reactive oxygen species (ROS)leads to the production of highly toxic hydroxyl radicals via theFenton reaction causing severe cell damage. Since increasedhepatic oxidative stress is considered a key factor in chronicHCV infection and coexists with increased levels of iron, progres-sion of liver disease by toxic radicals is very likely.

The underlying mechanisms of the hepatic iron accumulationin HCV-infected livers are still poorly understood and availabledata remain mostly descriptive: parenchymal iron accumulationin HCV patients has been linked to suppressed levels of the sys-temic iron hormone hepcidin [3,4]. These studies suggest thatiron accumulation by HCV is somehow comparable to hereditaryhemochromatosis where an inadequate hepcidin response toreplenished iron stores is a key feature [5] leading to unrestrictedduodenal iron absorption and iron release from macrophages viathe iron transporter ferroportin [6]. In addition, several othergenes previously not related to iron metabolism are also dis-cussed that potentially contribute to iron accumulation in HCV[7].

The work of Fillebeen and Pantopoulos in the present issue ofthe Journal of Hepatology leads the discussion about iron andHCV one step further, by demonstrating that iron directly blocksviral replication [8]. In the previous work the authors had shownthat iron can exert direct antiviral effects. Thus, iron binds tightly

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⇑ Tel.: +49 6221 483 210; fax: + 49 6221 484 494.E-mail address: Sebastian.Mueller@urz.uni-heidelberg.de

to NS5B, the RNA-dependent RNA polymerase of HCV, andinhibits its catalytic activity by displacing magnesium from theenzymatically active site [9]. The authors validated these findingsin a subgenomic HCV replicon model, where administration ofexogenous iron blocked viral replication and attenuated the pro-duction of viral RNA and proteins [9]. More interestingly, the datasuggested that expression of the subgenomic HCV replicon leadsto an iron-poor phenotype in host Huh7 cells, possibly to bypassthe iron-dependent block in viral replication [10]. In the presentissue of the Journal, they show that the administration of exoge-nous iron drastically inhibits the progression of HCV infection inpermissive Huh7.5.1 cells, obviously independent of the HCVgenotype.

These findings deserve particular attention in light of clinicaldata where HCV patients with hereditary iron overload, due tomutations in HFE, paradoxically respond better to antiviraltherapy [11–13]. Despite potential disturbances in macrophagefunction due to iron overload, it is tempting to speculate thatincreased hepatic iron content may contribute to viral RNA clear-ance and antagonize the relapse of HCV infection following ther-apy (Fig. 1). Fillebeen and Pantopoulos suggest, in anotherpublication [10], that HCV-infected hepatocytes tend to accumu-late iron which suppresses viral infection while the virus hasstrategies to eliminate iron (Fig. 1). While increasing intracellulariron levels reduced HCV replication, preloading of Huh7.5.1 cellswith iron failed to protect them against HCV infection, suggestingthat the iron bound to ferritin is unavailable for binding to NS5Band the active agent is free intracellular iron only. To achieve spe-cific intracellular iron loading and to avoid potentially confound-ing effects of heme oxygenase 1, the authors used a specific cellpermeable iron donor (Fe-SIH) instead of the routinely usediron-donor hemin. This specific iron donor may also explain themore profound effects on viral replication as compared to previ-ous reports using FeCl3 or iron-loaded lactoferrin.

Why then does iron overload secondary to HCV or otherchronic liver diseases such as alcoholic liver disease not improve,but rather worsen the clinical outcome?

Iron-induced oxidative stress very likely plays a major role.Iron is known to affect immune responses and cytokine produc-tion [14]. Moreover, the distribution of hepatic iron varies consid-erably between primary and secondary iron overload states andcould also affect the clinical outcome. Thus, in hereditary

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Fig. 1. Iron accumulation of an HCV-infected hepatocyte as an antiviralstrategy? Among other sources, ROS are generated by NADPH-dependentoxidases of innate immune cells (NOX1) and hepatocytes (NOX4) in HCV infectedlivers. This oxidative stress eventually leads to intracellular iron accumulation viasuppressed hepcidin or activation of IRP1 or TfR1. This iron can clear thehepatocyte from the virus since iron is a potent inhibitor of viral replication. Incontrast, infection with the hepatitis C virus leads to an iron-depleted hepatocytephenotype via still unknown mechanisms. IRP1, iron regulatory protein 1, TfR1,transferrin receptor 1.

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hemochromatosis, iron is almost exclusively deposited in paren-chymal cells while in secondary iron overload, including transfu-sional siderosis, excess iron is stored mainly in macrophages. Thismay explain why excess iron appeared to improve antiviral ther-apy in HCV-infected patients with hereditary hemochromatosis[11–13] but not in patients with secondary iron overload suchas ß-thalassemia [15]. Likewise, intravenous iron administrationdoes not improve the virological response of hemodialyzedHCV-infected patients to antiviral therapy [16]. Consequently,the inhibitory effects of iron on HCV replication may not beexploitable for simple treatment strategies. This complex situa-tion may also explain why studies, that analyzed the beneficialeffects of iron depletion (phlebotomy) on the progression ofHCV, reported contradictory results and still warrant confirma-tion in larger cohorts [17,18].

What could be the molecular mechanisms driving iron accu-mulation in chronic HCV infection? Interestingly, ROS do not onlycontribute to the toxicity of iron but can directly lead to its intra-cellular accumulation using specific signaling sequences. This hasbeen demonstrated at various regulatory levels e.g. via activationof iron regulatory protein 1 [19], suppression of hepcidin [20], ordirect translational activation of transferrin receptor 1 [21]. Theconcept summarized in Fig. 1 suggests that hepatocytes activelyaccumulate iron via specific ROS-induced mechanisms as partof their innate antiviral immunity while the virus has found

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evolutionary strategies to suppress iron accumulation via stillunknown mechanisms. Much more needs to be learnt about thedetailed molecular mechanisms of iron accumulation and ROSgeneration during HCV infection. Unraveling where protectiveiron accumulation turns into harmful iron overload will be oneof the challenging tasks for the future. Only then we will be ableto use the modulation of iron metabolism wisely in order to sup-port antiviral strategies.

Conflict of interest

The author declared that he does not have anything to discloseregarding funding or conflict of interest with respect to thismanuscript.

References

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