The 'Red Queen' dilemma - Running to stay in the same place: Reflections on the evolutionary vector of HBV in humans

Background: Estimates for the evolutionary rate of HBV until now have been interpreted as showing that HBV is a relatively recent acquisition for mankind. The existence of defined HBV genotypes is thought to represent past founder effects. We have explored virus mutation in a group of 48 persistently infected blood donors sampled at two points in time and suggest otherwise. Methods: HBV-infected donors were detected by hepatitis B surface antigen (HBsAg) screening and staged by hepatitis B e markers. Serum DNA from those persistently infected with HBV was characterized by consensus sequencing and the amino acid sequences inferred. These were compared against consensus genotype sequences and divergence measured at two points in time. Results: Rates of viral mutation were higher across both HBsAg and hepatitis B core antigen in the group of donors seropositive for hepatitis B e antibody (1.36×10^-3 and 1.54×10^-3 changes per residue per year, respectively) than in those seropositive for hepatitis B e antigen (4.59×10^-4 and 6.62×10^-4 changes per residue per year, respectively). Codon mutations reverting to the genotype consensus were commonly seen. Codon changes were clustered close to the C-terminal region of HBsAg and were accommodated in overlapping polymerase by synonymous substitutions. Conclusions: It is suggested that in vivo HBV behaves as a self-normalizing meme and mutational rates, although high, do not lead to significant change over time in a persistent infection. This would be compatible with co-evolution within its human host and introduction within humans being an ancient occurrence.