NATURALLY-OCCURRING HEPATITIS-B VIRUS CORE GENE-MUTATIONS

Mutations in the hepatitis B virus (HBV) core gene may influence disea se activity by altering immune recognition sites or level of virus rep lication. Sera from 69 Chinese patients with chronic HBV infection wer e analyzed by direct sequencing of polymerase chain reaction amplifica tion of NBV DNA to determine the frequency and location of naturally o ccurring HBV core gene mutations. All but one patient had nucleotide c hanges, and 44 (64%) patients had at least one amino acid change (mean , 3.7; range, 1-13) when compared with published sequences. Multiple r egression analysis showed that the frequency of core gene mutations wa s significantly associated with precore stop-codon mutation, hepatitis B e antigen negativity, and active liver disease, but not patients' a ge. The mean number of amino acid changes/ patient for hepatitis B e a ntigen (HBeAg)-positive patients with elevated versus normal aminotran sferase levels were, respectively, 2.8 +/- 0.4 and 0.6 +/- 0.2. The co rresponding values for HBeAg-negative patients were, respectively, 5.0 +/- 1.2 and 6.0 +/- 1.5. Thirteen patients were serially studied, the mean rates of amino acid substitution in HBeAg-positive patients who did or did not clear HBeAg during follow-up were 5.7 +/- 0.8 and 0 per codon/yr. Most of the mutations were clustered in the middle of the c ore gene that harbor several major B- and helper T-cell epitopes. Very few mutations were found in the C-terminal part of the core gene. In summary, mutations in the core gene can be frequently detected in pati ents with chronic HBV infection. These mutations occur predominantly a round the time of HBeAg clearance when liver disease is most active.