Selection of hepatitis B virus variants with aminoacid substitutions inside the core antigen during interferon-alpha therapy

The hepatitis B virus (HBV) core antigen carries many epitopes relevant for B and T cell response that show aminoacid variation during viral infection . In a longitudinal analysis, sequential serum samples of 15 patients that suffered from chronic HBV infection were collected before, during, and afte r high-dose IFN-alpha treatment. The HBV preCore/Core (preC/C) sequence of the selected samples in each patient was determined and analysed for sequen ce variations compared to the pretreatment sample. The positions of HBV cor e aminoacid substitutions were assigned to immunodominant B, CD4(+) and CD8 (+) cell epitopes. Seventy-five percent of all aminoacid substitutions were found within immunodominant T and B cell epitopes (12.5% were inside known HBV core mutation cluster regions) that show an increased number of cluste red aminoacid substitutions during chronic HBV infection and overlap partia lly with the immunodominant epitopes. Only 12.5% of the detected core antig en aminoacid substitutions could not be assigned to any epitope or mutation cluster region. Stable HBV core antigen aminoacid substitutions, which wer e found between pretreatment sequence and the last sequence analysed during therapy, were found most frequently inside T helper cell epitopes. This lo ngitudinal analysis of aminoacid substitutions inside the HBV core antigen in patients with chronic HBV infection shows that core aminoacid variations occur most frequently inside immunodominant HBV core epitopes, possibly du e to an immune-selective pressure of the host against the virus. The data a lso suggest that stable HBV variants with aminoacid substitutions in immuno dominant core epitopes can be selected during high-dose IFN-alpha therapy a nd persist after the end of treatment. J. Med. Virol. 62:479-486, 2000. (C) 2000 Wiley-Liss, Inc.