Genetic heterogeneity of the envelope 2 gene and eradication of hepatitis C virus after a second course of interferon-alpha.

The heterogeneity of the envelope 2 (E2) gene of the hepatitis C virus (HCV) was involved in the sensitivity of HCV to interferon-alpha (IFN-alpha). To assess the factors leading to virus eradication by IFN-alpha, patients whose first treatment by IFN-alpha failed and who had virus eradication after a second treatment were studied. These patients were paired with subjects in whom both treatments failed. The phosphorylation homology domain of the E2 gene (E2-PHD) had no sequence variation between the two stages in both groups of patients. Therefore, this region has no clinical predictive value within a specific genotype. The hypervariable region 1 (HVR1) was analyzed by cloning and sequencing 20 clones per sample. Comparison of samples showed that the change in quasispecies induced by the first IFN-alpha therapy could be associated with virus elimination obtained after a second treatment. The greater proportion of nonsynonymous mutations that was noted before the second treatment in responders suggest that pretherapeutic immune response is a major factor determining virus elimination and that the immune status of these patients changed between the first and the second treatment.