Increased iron in HCV infection: Collateral damage or antiviral defense?
Article Outline
Despite two decades of research in antiviral therapy, we still have not overcome a roughly 50% failure rate in the treatment of patients infected with the hepatitis C virus (HCV). Understanding the interactions between host and virus seems to be a prerequisite for any new therapeutic approach. Multiple axes of interaction have been suggested: cytokines, alterations of intracellular signaling and metabolism e.g. of fatty acids. An imbalanced iron homeostasis is another one: pathological iron deposits have been observed 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 of hepatocellular cancer (HCC) in HCV-infected patients [1]. In addition, we have learnt from hereditary hemochromatosis that iron overload is one of the most profibrogenic and carcinogenic factors 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 the Fenton reaction causing severe cell damage. Since increased hepatic oxidative stress is considered a key factor in chronic HCV infection and coexists with increased levels of iron, progression of liver disease by toxic radicals is very likely.
The underlying mechanisms of the hepatic iron accumulation in HCV-infected livers are still poorly understood and available data remain mostly descriptive: parenchymal iron accumulation in HCV patients has been linked to suppressed levels of the systemic iron hormone hepcidin [3], [4]. These studies suggest that iron accumulation by HCV is somehow comparable to hereditary hemochromatosis where an inadequate hepcidin response to replenished iron stores is a key feature [5] leading to unrestricted duodenal iron absorption and iron release from macrophages via the iron transporter ferroportin [6]. In addition, several other genes previously not related to iron metabolism are also discussed that potentially contribute to iron accumulation in HCV [7].
The work of Fillebeen and Pantopoulos in the present issue of the Journal of Hepatology leads the discussion about iron and HCV one step further, by demonstrating that iron directly blocks viral replication [8]. In the previous work the authors had shown that iron can exert direct antiviral effects. Thus, iron binds tightly to NS5B, the RNA-dependent RNA polymerase of HCV, and inhibits its catalytic activity by displacing magnesium from the enzymatically active site [9]. The authors validated these findings in a subgenomic HCV replicon model, where administration of exogenous iron blocked viral replication and attenuated the production of viral RNA and proteins [9]. More interestingly, the data suggested that expression of the subgenomic HCV replicon leads to an iron-poor phenotype in host Huh7 cells, possibly to bypass the iron-dependent block in viral replication [10]. In the present issue of the Journal, they show that the administration of exogenous iron drastically inhibits the progression of HCV infection in permissive Huh7.5.1 cells, obviously independent of the HCV genotype.
These findings deserve particular attention in light of clinical data where HCV patients with hereditary iron overload, due to mutations in HFE, paradoxically respond better to antiviral therapy [11], [12], [13]. Despite potential disturbances in macrophage function due to iron overload, it is tempting to speculate that increased hepatic iron content may contribute to viral RNA clearance and antagonize the relapse of HCV infection following therapy (Fig. 1). Fillebeen and Pantopoulos suggest, in another publication [10], that HCV-infected hepatocytes tend to accumulate iron which suppresses viral infection while the virus has strategies to eliminate iron (Fig. 1). While increasing intracellular iron levels reduced HCV replication, preloading of Huh7.5.1 cells with iron failed to protect them against HCV infection, suggesting that the iron bound to ferritin is unavailable for binding to NS5B and the active agent is free intracellular iron only. To achieve specific intracellular iron loading and to avoid potentially confounding effects of heme oxygenase 1, the authors used a specific cell permeable iron donor (Fe-SIH) instead of the routinely used iron-donor hemin. This specific iron donor may also explain the more profound effects on viral replication as compared to previous reports using FeCl3 or iron-loaded lactoferrin.
Fig. 1.
Iron accumulation of an HCV-infected hepatocyte as an antiviral strategy? Among other sources, ROS are generated by NADPH-dependent oxidases of innate immune cells (NOX1) and hepatocytes (NOX4) in HCV infected livers. This oxidative stress eventually leads to intracellular iron accumulation via suppressed hepcidin or activation of IRP1 or TfR1. This iron can clear the hepatocyte from the virus since iron is a potent inhibitor of viral replication. In contrast, infection with the hepatitis C virus leads to an iron-depleted hepatocyte phenotype via still unknown mechanisms. IRP1, iron regulatory protein 1, TfR1, transferrin receptor 1.
Why then does iron overload secondary to HCV or other chronic 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 production [14]. Moreover, the distribution of hepatic iron varies considerably between primary and secondary iron overload states and could also affect the clinical outcome. Thus, in hereditary hemochromatosis, iron is almost exclusively deposited in parenchymal cells while in secondary iron overload, including transfusional siderosis, excess iron is stored mainly in macrophages. This may explain why excess iron appeared to improve antiviral therapy in HCV-infected patients with hereditary hemochromatosis [11], [12], [13] but not in patients with secondary iron overload such as ß-thalassemia [15]. Likewise, intravenous iron administration does not improve the virological response of hemodialyzed HCV-infected patients to antiviral therapy [16]. Consequently, the inhibitory effects of iron on HCV replication may not be exploitable for simple treatment strategies. This complex situation may also explain why studies, that analyzed the beneficial effects of iron depletion (phlebotomy) on the progression of HCV, reported contradictory results and still warrant confirmation in larger cohorts [17], [18].
What could be the molecular mechanisms driving iron accumulation in chronic HCV infection? Interestingly, ROS do not only contribute to the toxicity of iron but can directly lead to its intracellular accumulation using specific signaling sequences. This has been demonstrated at various regulatory levels e.g. via activation of iron regulatory protein 1 [19], suppression of hepcidin [20], or direct translational activation of transferrin receptor 1 [21]. The concept summarized in Fig. 1 suggests that hepatocytes actively accumulate iron via specific ROS-induced mechanisms as part of their innate antiviral immunity while the virus has found evolutionary strategies to suppress iron accumulation via still unknown mechanisms. Much more needs to be learnt about the detailed molecular mechanisms of iron accumulation and ROS generation during HCV infection. Unraveling where protective iron accumulation turns into harmful iron overload will be one of the challenging tasks for the future. Only then we will be able to use the modulation of iron metabolism wisely in order to support antiviral strategies.
Conflict of interest
The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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PII: S0168-8278(10)00721-X
doi:10.1016/j.jhep.2010.08.003
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells , 02 August 2010
