Hepatitis C virus, the E2 envelope protein, and alpha-interferon resistance.

Envelope Protein, and a-Interferon Resistance Taylor et al. (1) showed that the hepatitis C virus (HCV) envelope protein E2 inhibits the activity of the interferon-inducible protein kinase PKR in cell systems. PKR is an antiviral protein that blocks protein synthesis by phosphorylating the translation initiation factor eIF2a (2). HCV E2 binds to PKR through a 12–amino acid sequence similar to the PKR autophosphorylation site and the eIF2a phosphorylation site, the PKR-eIF2a phosphorylation homology domain (PePHD). This binding and inhibition may account for the intrinsic resistance to interferon (IFN) therapy of chronic hepatitis C patients infected with genotype 1, but not of those with genotypes 2 or 3, in agreement with clinical data (3). To assess whether the E2 PePHD sequence may be specifically associated with a pattern of response to a-IFN that may have diagnostic and prognostic significance, we studied 15 patients with chronic hepatitis C. Response to a-IFN was defined as lack of serum HCV RNA (by qualitative RT-PCR; Amplicor, Roche, Switzerland) after 12 weeks of treatment at a dose of 3 MU three times a week. Eight patients— two responders and six nonresponders— belonged to HCV genotype 1; seven patients—five responders and two nonresponders— belonged to genotype 3 (Fig. 1). Complementary DNA derived from total liver RNA was PCR-amplified using Pfu polymerase and primers encompassing the COOH-terminal E2-encoding region of HCV. Purified PCR products were directly sequenced and analyzed by multiple sequence alignment with hierarchical clustering (4). All eight HCV genotype 1 isolates, irrespective of the pattern of response to a-IFN, had the same consensus sequence, corresponding to that of the IFN-resistant patient belonging to genotype 1b in the Taylor et al. study [figure 1 of (1)]. The consensus sequences of HCV genotype 3 isolates were also identical in all but two patients, again irrespective of the response to a-IFN. These results show that the PePHD sequence may not necessarily account for the pattern of response to a-IFN in vivo. The failure to respond of two patients infected with HCV genotype 3 may have stemmed from an insufficient dose of a-IFN (5). By contrast, the response to treatment of two patients infected with HCV genotype 1, despite a PePHD sequence identical to that of a-IFN–resistant HCV isolates, suggests that other factors may have had a greater influence on the response to a-IFN. The interaction between HCV-E2 and PKR may well affect the PKR activity, but that activity may not be entirely suppressed if the baseline state is highly activated. We do not dismiss the elegant data obtained by Taylor et al. in cell systems (1). Steadfast application of those results to the human model may be premature, however, until the appropriate correlative studies have been made.