Role of viral and host factors in HCV persistence: which lesson for therapeutic and preventive strategies?

Several lines of evidence support the view that hepatitis C virus is not directly cytopathic for infected host cells and that the immune response plays a central role in the pathogenesis of liver damage. Innate and adaptive immune responses are induced in most individuals infected with hepatitis C virus but are insufficient to eliminate the virus. The mechanisms responsible for this failure are largely unknown but the kinetics of hepatitis C virus replication relative to the priming of the adaptive responses may exert a profound influence on the balance between virus and host. Immediately after hepatitis C virus infection, the virus replicates efficiently, inducing the production of type I interferons. However, the rapid increase in viral replication seems to be ignored by the adaptive immune response, and after a short interval from exposure, viral load can reach levels comparable to those of patients with established persistent infection. The CD8-mediated response shows functional defects, with impaired production of interferon-gamma, low perforin content, decreased capacity of expansion and lysis of target cells. Late appearance and functional defects of T cells in hepatitis C virus infection might be the result of the rapid increase of the viral load that could create the conditions for exhaustion of the adaptive response or reflect an insufficient function of the innate immune response. This possibility is suggested by in vitro studies showing that hepatitis C virus gene products can interfere with the anti-viral activity of type I interferons and natural killer cells as well as with the maturation of dendritic cells. While T-cell defects are reversed in a minority of infected individuals who succeed in controlling the infection, the T-cell impairment becomes progressively more profound as infection progresses to chronicity. In this situation, therapeutic restoration of adaptive responses may represent a rational strategy to obtain resolution of infection and to complement available therapies. The peculiar kinetics of hepatitis C virus replication and T-cell induction soon after infection may have important implications also for the design of protective vaccines since memory responses may not be able to precede the early peak of viral replication. Therefore, vaccines against hepatitis C virus may be unable to prevent infection but may rather be effective in facilitating a self-limited evolution of infection. (C) 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.