Does nitric oxide play a pathogenic role in hepatitis C virus infection?

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In spite of important progress in understanding the mechanisms of hepatitis C virus (HCV) pathogenesis in the last decade, we still lack firm experimental evidence to explain the two major features of the natural history of this viral infection: viral persistence and hepatic damage. Nevertheless, recent information from both in vitro HCV replication systems and animal models of HCV infection have led to a plethora of critical observations showing that host immune responses play a critical role influencing the outcome of HCV-induced liver disease, such as favoring virus persistence and by mediating liver cell injury.1 In an attempt to reconcile these apparently opposite pathogenic pathways, the increasing evidence that nitric oxide (NO) is one of the most versatile mediators in the control of viral infections, being the earliest host's antiviral response2, as well as in the pathogenesis of many human infectious and inflammatory diseases,3,4 acting as a pro-apoptotic inducer in some cell types or as an anti-apoptotic modulator in other cell types including hepatocytes,5 makes it reasonable to consider this multifunctional molecule as a potential player in HCV pathogenesis. This notion has been reinforced since the observation in the liver of HCV-infect ed patients of an enhanced iNOS expression, implying an excessive NO formation, positively correlated with viral load and hepatic inflammation.6,7,8 The ultimate effect of iNOS-derived NO on HCV pathogenesis, however, still remains far from completely understood but, in this commentary, we will try to shed light on the NO paradox in the pathogenesis of HCV infection.