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A New Look at Interferon Resistance

Hepatitis C is an emerging virus of great medical importance and almost always causes chronic infections. The current available treatment options for chronic HCV include the use of interferon, but many HCV isolates are resistant. In the United States 70% of all HCV infections are genotype 1, which is the most resistant genotype to treatment.

Interferon normally acts by inducing transcription of several antiviral genes, including the double-stranded RNA-activated protein kinase (PKR), which inhibits protein synthesis by phosphorylation of the translation initiation factor eIF2 alpha. Many viruses have evolved strategies to overcome the antiviral effects of PKR. One of the HCV nonstructural proteins, NS5A, has been shown to bond to and inhibit PKR; however, the NS5A-PKR interaction can explain only those cases of interferon resistance that exhibit NS5A quasispecies divergence after interferon therapy. Based on this information how do we explain the resistance of genotype 1 HCV versus other genotypes in untreated patients?

A recent study focused on E2, an outer protein of the viral envelope. E2 shows considerable variation among different HCV isolates, and it induces neutralizing antibodies. E2 from most isolates contains a 12-amino acid sequence that is similar to the PKR-eIF2 alpha site. The sequences of the more interferon resistant HCV genotypes (1a and1b) more closely resemble the sequences of PKR and eIF2 alpha than do corresponding sequences of the less resistant genotypes (2a, 2b, and 3a) The results of this new study suggest that the E2 protein of HCV genotype 1 binds to and inhibits PKR in vitro and does so in mammalian cells because of sequence homology to the PKR and eIF2 alpha phosphorylation sites. These effects correlate with the relative resistance of the HCV genotype 1 to interferon. Thus, HCV may have evolved a two-level attack, namely NS5A and E2, on PKR to interfere with interferon action. Although these results potentially are very interesting, the area of HCV resistance will require ongoing investigation.

D.R.Taylor, S.T.Shi, P.R. Romano, G.N. Barber, M.M.C. Lai; Science July 2, 1999,(5424):107


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