Long-term mutation rates in the hepatitis B virus genome

Mutations in the hepatitis B virus (HBV) genome have so far been investigat ed in cross-sectional or short-term longitudinal studies. Information about long-term changes is lacking due to the difficulty of sampling over long o bservation periods. In this study, a retrospective approach was used that a llowed the analysis of changes in the viral genome from transmission to lat e stages of infection without the requirement for sampling early during thi s period. The entire viral genome was sequenced from serum samples of three mothers and their 10 adult children, who presumably had been infected vert ically, The emergence of mutations between birth and sampling (mean 26.5 ye ars) was assessed by comparing the individual sequences with the sequence o f the strain assumed to have been transmitted, The mean differences from th is sequence were 0.02 and 0.28% in seven asymptomatic and one symptomatic h epatitis B e antigen (HBeAg)-positive carriers, respectively, and 0.62 % in five HBeAg-negative carriers. Mutations occurred throughout the genome and 88% of the mutations caused amino acid substitutions spread over all genes , In HBeAg-negative carriers, the number of nucleotide and amino acid chang es was independent of the severity of liver disease and, except the (1762)A GG(1764) --> TGA changes, no specific mutation was associated with river di sease, in conclusion, by using a novel method it was found that the entire HBV genome is extremely stable over long periods of time during the HBeAg-p ositive phase if the immune response (inflammation) is weak, whereas an ave rage of 20 mutations emerged after development of hepatitis and/or loss of HBeAg without association with clinical outcome.