Interfering with interferon

Abstract

Chronic hepatitis C virus (HCV) infection is a major clinical problem in many countries, partly because of the resistance to interferon (IFN) therapy of some HCV genotypes. A small, 40 amino acid domain in the HCV non-structural (NS)5A protein, called the interferon sensitivity determining region (ISDR), has been associated with a lack of response to IFN in Japanese patients infected with HCV genotype 1b. Mutations within the ISDR appear to make the virus vulnerable to IFN therapy (e.g. Ref. 1 Enomoto N. et al. Mutations in the nonstructural protein 5A and response to interferon in patients with chronic hepatitis C virus 1b infection. New Engl. J. Med. 1996; 334: 77-81 Crossref PubMed Scopus (980) Google Scholar ). It has also been shown that NS5A interacts with the IFN-induced protein kinase, PKR, to inhibit the kinase activity 2 Gale M.J. et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997; 230: 217-227 Crossref PubMed Scopus (719) Google Scholar . Other viruses, such as poliovirus, HIV, adenovirus, influenza virus and vaccinia virus also specifically inhibit PKR during viral replication; hence, it appears that at least one of NS5A’s functions is to counteract cellular defenses. Furthermore, the NS5A–PKR interaction has been shown to require the ISDR – mutations within the ISDR, which are associated with IFN sensitivity, abolish this interaction 3 Gale M. et al. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol. Cell. Biol. 1998; 18: 5208-5218 Crossref PubMed Scopus (556) Google Scholar . However, these findings have not been substantiated by clinical studies from Europe (e.g. Ref. 4 Duverlie G. et al. Sequence analysis of the NS5A protein of European hepatitis C virus 1b isolates and relation to interferon sensitivity. J. Gen. Virol. 1998; 79: 1373-1381 PubMed Google Scholar ) and North America (e.g. Ref. 5 Chung R.T. et al. Mutations in the NS5A region do not predict interferon-responsiveness in American patients infected with genotype 1b hepatitis C virus. J. Med. Virol. 1999; 58: 353-358 Crossref PubMed Scopus (69) Google Scholar ). In some instances, NS5A-mediated IFN resistance might involve the ISDR–PKR interaction, but IFN resistance might also map to other regions of NS5A or other HCV proteins.