Reply to: Is there any association between HCV multiplication and iron induced liver injury in chronic hepatitis C?

Is there any association between HCV multiplication and iron induced liver injury in chronic hepatitis C?Journal of HepatologyVol. 55Issue 1PreviewWe were very interested in the excellent paper by Fillebeen et al. published in a recent issue of the Journal of Hepatology [1]. The paper presents unexpected results on the role of iron in hepatitis C virus (HCV) replication. The authors confirm the results of a previous publication and show, in in vitro experiments, the iron-mediated inhibition of HCV replication. Full-Text PDF Open Access We appreciate the interest of Sikorska et al. in our recent study [[1]Fillebeen C. Pantopoulos K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells.J Hepatol. 2010; 53: 995-999Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] and would like to comment on the issues raised in their letter. We fully agree that, in light of clinical literature and earlier biochemical evidence, the iron-mediated inhibition of HCV replication is surprising. This matter has been extensively discussed in a previous related publication [[2]Fillebeen C. Rivas-Estilla A.M. Bisaillon M. Ponka P. Muckenthaler M. Hentze M.W. et al.Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus.J Biol Chem. 2005; 280: 9049-9057Crossref PubMed Scopus (88) Google Scholar], which established that iron attenuates the expression of subgenomic HCV replicons in culture and blocks the enzymatic activity of recombinant HCV polymerase NS5B in vitro. Our recent study validated the antiviral activity of iron in a more physiologically relevant setting of infectious HCV in permissive Huh7.5.1 cells. Certainly, HCV replicon models do not recapitulate the entire range of molecular responses triggered in the host during acute infection with HCV and progression to CHC; nevertheless, they provide a valuable framework to elucidate important aspects of HCV biology in a reductionist approach. The employment of such models uncovered that iron inhibits HCV replication. We speculated that this surprising finding may account for some unexpected clinical observations, where HCV-infected patients with mutations in the HFE gene responded better to antiviral therapy [3Distante S. Bjoro K. Hellum K.B. Myrvang B. Berg J.P. Skaug K. et al.Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.Liver. 2002; 22: 269-275Crossref PubMed Scopus (73) Google Scholar, 4Bonkovsky H.L. Naishadham D. Lambrecht R.W. Chung R.T. Hoefs J.C. Nash S.R. et al.Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.Gastroenterology. 2006; 131: 1440-1451Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 5Lebray P. Zylberberg H. Hue S. Poulet B. Carnot F. Martin S. et al.Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C.J Viral Hepat. 2004; 11: 175-182Crossref PubMed Scopus (41) Google Scholar].Sikorska et al. challenge this idea by arguing that it is merely supported by selected reports. We believe that published clinical literature qualifies to accommodate hypotheses arising from biochemical data. Moreover, we wish to emphasise that an increased frequency of HFE gene mutations in HCV patients who are responders to antiviral therapy has been documented in major clinical studies (reviewed in [[6]Sebastiani G. Walker A.P. HFE gene in primary and secondary hepatic iron overload.World J Gastroenterol. 2007; 13: 4673-4689Crossref PubMed Scopus (116) Google Scholar]). Thus, in a cohort of 256 CHC patients, the presence of HFE C282Y mutation positively correlated with sustained response in multivariate analysis (p = 0.012) [[3]Distante S. Bjoro K. Hellum K.B. Myrvang B. Berg J.P. Skaug K. et al.Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.Liver. 2002; 22: 269-275Crossref PubMed Scopus (73) Google Scholar]. Likewise, CHC patients with HFE H63D mutation showed a significant improvement in both their primary response and sustained response to interferon, although statistical significance for the latter did not reach the level of 0.05 [[5]Lebray P. Zylberberg H. Hue S. Poulet B. Carnot F. Martin S. et al.Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C.J Viral Hepat. 2004; 11: 175-182Crossref PubMed Scopus (41) Google Scholar]. These data suggested that HFE may constitute part of a battery of host genes that affect responses to antiviral therapy. Similarly, in the largest study thus far, on the effects of HFE-related iron overload in anti-HCV therapy (HALT-C trial) that included 1051 patients, Bonkovsky et al. found that subjects harboring HFE mutations, particularly H63D, had significantly higher likelihood of both end-of-treatment virological response (p = 0.0078) and sustained virological response (p = 0.009) to re-treatment with pegylated interferon alpha-2α plus ribavirin [[4]Bonkovsky H.L. Naishadham D. Lambrecht R.W. Chung R.T. Hoefs J.C. Nash S.R. et al.Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.Gastroenterology. 2006; 131: 1440-1451Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. Again, both the HFE mutation and/or associated genetic variants were considered as possible causes of the improved response to therapy.The iron-dependent inhibition of HCV replication documented in our studies is consistent with the above clinical findings and it is tempting to speculate that even minimal HFE-related hepatic iron overload may contribute to viral clearance in HCV-infected patients subjected to antiviral treatment. There is no doubt that this hypothesis requires further validation in animal models of HCV infection. It should also be noted that the adverse effects of iron overload in the liver and in the immune system preclude any exploitation of the iron-dependent inhibition of HCV replication for therapeutic purposes.Conflict of interestThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We appreciate the interest of Sikorska et al. in our recent study [[1]Fillebeen C. Pantopoulos K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells.J Hepatol. 2010; 53: 995-999Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] and would like to comment on the issues raised in their letter. We fully agree that, in light of clinical literature and earlier biochemical evidence, the iron-mediated inhibition of HCV replication is surprising. This matter has been extensively discussed in a previous related publication [[2]Fillebeen C. Rivas-Estilla A.M. Bisaillon M. Ponka P. Muckenthaler M. Hentze M.W. et al.Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus.J Biol Chem. 2005; 280: 9049-9057Crossref PubMed Scopus (88) Google Scholar], which established that iron attenuates the expression of subgenomic HCV replicons in culture and blocks the enzymatic activity of recombinant HCV polymerase NS5B in vitro. Our recent study validated the antiviral activity of iron in a more physiologically relevant setting of infectious HCV in permissive Huh7.5.1 cells. Certainly, HCV replicon models do not recapitulate the entire range of molecular responses triggered in the host during acute infection with HCV and progression to CHC; nevertheless, they provide a valuable framework to elucidate important aspects of HCV biology in a reductionist approach. The employment of such models uncovered that iron inhibits HCV replication. We speculated that this surprising finding may account for some unexpected clinical observations, where HCV-infected patients with mutations in the HFE gene responded better to antiviral therapy [3Distante S. Bjoro K. Hellum K.B. Myrvang B. Berg J.P. Skaug K. et al.Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.Liver. 2002; 22: 269-275Crossref PubMed Scopus (73) Google Scholar, 4Bonkovsky H.L. Naishadham D. Lambrecht R.W. Chung R.T. Hoefs J.C. Nash S.R. et al.Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.Gastroenterology. 2006; 131: 1440-1451Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 5Lebray P. Zylberberg H. Hue S. Poulet B. Carnot F. Martin S. et al.Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C.J Viral Hepat. 2004; 11: 175-182Crossref PubMed Scopus (41) Google Scholar]. Sikorska et al. challenge this idea by arguing that it is merely supported by selected reports. We believe that published clinical literature qualifies to accommodate hypotheses arising from biochemical data. Moreover, we wish to emphasise that an increased frequency of HFE gene mutations in HCV patients who are responders to antiviral therapy has been documented in major clinical studies (reviewed in [[6]Sebastiani G. Walker A.P. HFE gene in primary and secondary hepatic iron overload.World J Gastroenterol. 2007; 13: 4673-4689Crossref PubMed Scopus (116) Google Scholar]). Thus, in a cohort of 256 CHC patients, the presence of HFE C282Y mutation positively correlated with sustained response in multivariate analysis (p = 0.012) [[3]Distante S. Bjoro K. Hellum K.B. Myrvang B. Berg J.P. Skaug K. et al.Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.Liver. 2002; 22: 269-275Crossref PubMed Scopus (73) Google Scholar]. Likewise, CHC patients with HFE H63D mutation showed a significant improvement in both their primary response and sustained response to interferon, although statistical significance for the latter did not reach the level of 0.05 [[5]Lebray P. Zylberberg H. Hue S. Poulet B. Carnot F. Martin S. et al.Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C.J Viral Hepat. 2004; 11: 175-182Crossref PubMed Scopus (41) Google Scholar]. These data suggested that HFE may constitute part of a battery of host genes that affect responses to antiviral therapy. Similarly, in the largest study thus far, on the effects of HFE-related iron overload in anti-HCV therapy (HALT-C trial) that included 1051 patients, Bonkovsky et al. found that subjects harboring HFE mutations, particularly H63D, had significantly higher likelihood of both end-of-treatment virological response (p = 0.0078) and sustained virological response (p = 0.009) to re-treatment with pegylated interferon alpha-2α plus ribavirin [[4]Bonkovsky H.L. Naishadham D. Lambrecht R.W. Chung R.T. Hoefs J.C. Nash S.R. et al.Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.Gastroenterology. 2006; 131: 1440-1451Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. Again, both the HFE mutation and/or associated genetic variants were considered as possible causes of the improved response to therapy. The iron-dependent inhibition of HCV replication documented in our studies is consistent with the above clinical findings and it is tempting to speculate that even minimal HFE-related hepatic iron overload may contribute to viral clearance in HCV-infected patients subjected to antiviral treatment. There is no doubt that this hypothesis requires further validation in animal models of HCV infection. It should also be noted that the adverse effects of iron overload in the liver and in the immune system preclude any exploitation of the iron-dependent inhibition of HCV replication for therapeutic purposes. Conflict of interestThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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