The nature of interferon-alpha resistance in hepatitis C virus infection.
OBJECTIVE
HCV infection becomes chronic in 50-85% of cases. The treatment of chronic hepatitis C is currently based on a combination of pegylated interferon (IFN)-alpha and ribavirin. With this regimen, a failure to eradicate infection occurs in 18-24% of patients infected by genotype 2 or 3, and in 54-58% of patients infected by genotype 1. IFN resistance, i.e. the capacity of HCV strains to attenuate IFN antiviral responses in order to evade them, could play a role in the establishment of chronic infection at the acute stage of infection. IFN resistance could also play a role in the virological response to IFN therapy through similar or different mechanisms. The involved mechanisms however remain unclear.


RESULTS
Several viral proteins were recently shown to mediate IFN resistance through inhibition of IFN antiviral effectors in vitro, but the relevance of such mechanisms in vivo is not proven. Whatever the mechanisms, IFN resistance could play a role at the early stages of infection, but a qualitative and quantitative defect of both CD4-positive and CD8-positive immune responses appears as the main determinant of viral persistence. IFN treatment failure to eradicate infection is multifactorial. IFN resistance could play a partial role through unclear mechanisms. However, immune clearance of infected cells appears to be the principal determinant of IFN treatment success.


CONCLUSIONS
In spite of active research, the role and the mechanisms of IFN resistance in HCV persistence and IFN treatment failure remain partly unknown. A better understanding is needed in order to further improve IFN treatment strategies.
Pawlotsky
Jean-Michel
JM
Department of Virology, Henri Mondor Hospital, Paris XII University, Créteil, France. jean-michel.pawlotsky@hmn.ap-hop-paris.fr
D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure
D016898:Interferon-alpha