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 after high-dose IFN-alpha treatment. The HBV preCore/Core (preC/C) sequence of the selected samples in each patient was determined and analysed for sequence variations compared to the pretreatment sample. The positions of HBV core 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 clustered aminoacid substitutions during chronic HBV infection and overlap partially with the immunodominant epitopes. Only 12.5% of the detected core antigen aminoacid substitutions could not be assigned to any epitope or mutation cluster region. Stable HBV core antigen aminoacid substitutions, which were found between pretreatment sequence and the last sequence analysed during therapy, were found most frequently inside T helper cell epitopes. This longitudinal 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 due to an immuneselective pressure of the host against the virus. The data also suggest that stable HBV variants with aminoacid substitutions in immunodominant core epitopes can be selected during high-dose IFN-alpha therapy and persist after the end of treatment.