Naturally occurring hepatitis B virus genomes bearing the hallmarks of retroviral G → A hypermutation

Abstract

Two hypermutated genomes of hepatitis B virus (HBV) were cloned from sera of chronic virus carriers. Twelve percent and 26% of guanosine residues were replaced by adenosine, with the transitions being erratically distributed along the genome G → A substitutions showed a strong dinucleotide preference, decreasing in the order GpA > GpG ≤ GpC ≤ GpT. Such traits are typical of retroviral G → A hypermutation which results from cDNA synthesis coinciding with fluctuations in the intracellular [dTTP[/[dCTP[ ratio. The observations offer an explanation for the high prevalence of HBV variants bearing a tryptophan 28 → stop codon in the pre- core region of carriers with chronic active or fulminant hepatitis. The HBV hypermutants indicate that a small proportion of hepatocytes have distorted dNTP pools, which might have implications for the fidelity of hepatocyte DNA replication or repair.