Hepatocyte iron accumulation: A new string to ribavirin’s antiviral bow?
Authors: John D. Ryan, John Crowe
Journal: Journal of Hepatology (2011)

Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cellsJournal of HepatologyVol. 53Issue 6PreviewChronic 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. Full-Text PDF Reply to: Hepatocyte iron accumulation: A new string to ribavirin’s antiviral bow?Journal of HepatologyVol. 55Issue 1PreviewWe thank Drs. J.D. Ryan and J. Crowe for their comments to our recent article [1]. In their letter, they discuss earlier reports showing that prolonged treatment of HCV-infected patients with ribavirin associates with hepatic iron deposition, mainly in hepatocytes [2,3]. This is largely attributed to extravascular hemolysis, a known side effect of ribavirin ([2] and references therein) even though one would expect a predominant distribution of excess iron within Kupffer cells. The authors further hypothesize that accumulation of iron within hepatocytes may potentiate the antiviral efficacy of this therapeutic regimen, considering that iron inhibits the replication of HCV in permissive Huh7.5.1 cells [1]. Full-Text PDF Open Access Building on previous work, the recent article by Fillebeen and Pantopoulos elegantly demonstrates a role for iron as an inhibitor of hepatitis C virus (HCV) replication [[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 (54) Google Scholar]. Using HCV-infected Huh7.5.1 hepatoma cells, the authors show a dose-dependent reduction in the expression of HCV viral proteins and RNA upon exogenous administration of iron. Moreover, the anti-viral effect of iron was attributed to the direct inhibition of the HCV RNA polymerase NS5B by iron [[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 (89) Google Scholar]. However, the findings outlined in this article appear contrary to the prevailing perception of the role of iron in HCV infection. Disordered iron homeostasis is a frequent finding in HCV patients and may be associated with adverse clinical outcomes [[3]Piperno A. Vergani A. Malosio I. Parma L. Fossati L. Ricci A. et al.Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations.Hepatology. 1998; 28: 1105-1109Crossref PubMed Scopus (127) Google Scholar]. An increased propensity to hepatic decompensation, an increased incidence of hepatocellular carcinoma, and a reduced response to treatment have all been reported in association with excess serum or hepatic iron [4Fujita N. Sugimoto R. Urawa N. Araki J. Mifuji R. Yamamoto M. et al.Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C.J Gastroenterol Hepatol. 2007; 22: 1886-1893Crossref PubMed Scopus (88) Google Scholar, 5Bassett S.E. Bisceglie A.M.D. Bacon B.R. Sharp R.M. Govindarajan S. Hubbard G.B. et al.Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees.Hepatology. 1999; 29: 1884-1892Crossref PubMed Scopus (78) Google Scholar, 6Chapoutot C. Esslimani M. Joomaye Z. Ramos J. Perney P. Laurent C. et al.Liver iron excess in patients with hepatocellular carcinoma developed on viral C cirrhosis.Gut. 2000; 46: 711-714Crossref PubMed Scopus (77) Google Scholar]. The authors acknowledge these issues and conclude by doubting whether iron-mediated inhibition of HCV replication would represent a realistic therapeutic target. These sentiments were echoed in the accompanying editorial [[7]Mueller S. Increased iron in HCV infection: collateral damage or antiviral defense?.J Hepatol. 2010; 53: 990-992Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. The nucleoside analogue ribavirin forms a key component of the current standard of care for HCV treatment, in combination with pegylated interferon alpha. Despite its importance in augmenting treatment response and preventing relapse, its antiviral mechanism of action remains elusive [[8]Feld J.J. Hoofnagle J.H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C.Nature. 2005; 436: 967-972Crossref PubMed Scopus (846) Google Scholar]. Curiously, significant hepatic iron accumulation has been reported in HCV patients receiving ribavirin monotherapy for greater than 6 months [9Di Bisceglie A.M. Bacon B.R. Kleiner D.E. Hoofnagle J.H. Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic hepatitis C.J Hepatol. 1994; 21: 1109-1112Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 10Fiel M.I. Schiano T.D. Guido M. Thung S.N. Lindsay K.L. Davis G.L. et al.Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.Am J Clin Pathol. 2000; 113: 35-39Crossref PubMed Google Scholar]. These findings were attributed to the well-documented, dose-dependent haemolysis caused by ribavirin. However, excess iron accumulated predominantly in hepatocytes, rather than in phagocytic Kupffer cells, as might be expected following intravascular haemolysis [[10]Fiel M.I. Schiano T.D. Guido M. Thung S.N. Lindsay K.L. Davis G.L. et al.Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.Am J Clin Pathol. 2000; 113: 35-39Crossref PubMed Google Scholar]. Although hepatic iron accumulation during treatment was not associated with changes in liver transaminases, it is unclear whether treatment response was altered [[10]Fiel M.I. Schiano T.D. Guido M. Thung S.N. Lindsay K.L. Davis G.L. et al.Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.Am J Clin Pathol. 2000; 113: 35-39Crossref PubMed Google Scholar]. Iron accumulation in chronic HCV infection appears harmful. Given the findings by Fillebeen et al., it would be difficult to discount a potential role for iron in hepatocyte HCV eradication, which may be transiently facilitated by ribavirin therapy. At the very least, this potential mechanism of ribavirin action merits further investigation. GI Research fund, Mater Hospital. 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.