Hepatitis C virus after interferon treatment has the variation in the hypervariable region of envelope 2 gene

There is a hypervariable region in the envelope 2 gene of the hepatitis C virus genome, whose heterogeneity in different hepatitis C virus isolates has been suggested to be a result of the immune selection of escape variants. To determine the role of hypervariable region variants in the mechanism of resistance to interferon observed in 75-80% of interferon-treated patients with chronic hepatitis C, hypervariable region sequences were compared before and after interferon treatment. Eight patients with chronic hepatitis C were treated with recombinant interferon-alpha-2b. DNA containing the hypervariable region was obtained by reverse transcription-polymerase chain reaction from serial plasma samples of each patient and directly sequenced without cloning to determine changes in the predominant sequence. In two patients, hepatitis C virus-RNA was eliminated by interferon treatment. In the remaining six patients, hepatitis C virus-RNA was not eradicated. The predominant hepatitis C virus which survived interferon treatment was the mutant hepatitis C virus with 3-19 out of 81 nucleotide substitutions in the hypervariable region, resulting in 2-14 out of 27 amino acid changes. Most of the nucleotide substitutions were nonsynonymous, indicating that there were positive selections for amino acid changes in the hypervariable region. The change rate was significantly higher in patients whose plasma hepatitis C virus-RNA was consistently detectable during and after interferon treatment than in patients whose plasma hepatitis C virus-RNA became undetectable during treatment and reappeared after the cessation of the treatment (4.23 +/- 0.43 vs 0.77 +/- 0.20 x 10(-1)/site/year, p < 0.01). This suggests that the evolution of the hypervariable region was associated with the effect of interferon treatment. These results suggest that hypervariable region variants play an important role in maintaining persistent infection during interferon treatment by evading host immune surveillance.