Substitution rate of the hepatitis B virus surface gene.
Molecular epidemiology of hepatitis B virus (HBV) often relies on the comparison of HBV surface (S) gene sequences, although little is known about the substitution rate of the HBV S-gene. In this study, we compared HBV S-gene sequences in longitudinal sample pairs of 40 untreated, chronically HBV-infected patients, spanning 210 years of cumulative follow-up. The 40 patients included HBV e-antigen positive and negative persons; with HBV DNA levels ranging from 10(3) to 10(9) cps/mL and belonging to HBV genotypes A, B, C, D and E. In the 40 sample pairs, 70 nucleotide changes occurred in the HBV S-gene (0-8 per patient), resulting in an average substitution rate of 5.1 x 10(-4) nucleotide changes/site/year (range: 0-1.3 x 10(-2)). Surprisingly, the number of substitutions was strongly associated with the inverse level of viremia; and only weakly with the duration of follow-up: in 11 highly viremic patients (HBV DNA > or =10(8) cps/mL), only four substitutions occurred despite a cumulative observation period of 56 years (substitution rate: 1.1 x 10(-4)), while in the 10 patients with viremia below 10(4) cps/mL, 29 substitutions occurred during 30 years of follow-up (substitution rate: 14.6 x 10(-4)). We conclude that in chronic hepatitis B virus infection the rate of nucleotide substitution in the HBV S-gene is inversely related to the level of viremia and thus varies widely from person to person; hampering the phylogenetic analysis of possible chains of HBV infection.
Zaaijer
H L
HL
Academic Medical Center (AMC - CINIMA), Clinical Virology, University of Amsterdam, Amsterdam, The Netherlands. h.l.zaaijer@amc.uva.nl
Bouter
S
S
Boot
H J
HJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000302:isolation & purification*; D019694:Hepatitis B, Chronic / Q000821:virology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D019562:Viral Load; D014766:Viremia
D006514:Hepatitis B Surface Antigens