Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion

Background & Aims Although the evolution of viral quasi-species may be related to the pathological status of disease, little is known about this phenomenon in hepatitis B, particularly with respect to hepatitis B e antigen (HBeAg) seroconversion. Methods Nucleotide sequences of the hepatitis B virus (HBV) X / precore/core region was analyzed at five time-points in four groups of chronic hepatitis B patients, interferon-induced seroconverters (IS, N = 9), interferon non-responders (IN, N = 9), spontaneous seroconverters (SS, N = 9), and non-seroconverters (SN, N = 9) followed during 60 months on an average. Only patients with genotype C were studied. Results Analysis of 1800 nucleotide sequences showed that there was no statistical difference between the nucleotide genetic distances of seroconverters (IS and SS; 6.9 × 10−3 substitutions (st)/site and 6.7 × 10−3 st/site, respectively) and those of non-seroconverters (IN and SN; 5.3 × 10−3 st/site and 3.8 × 10−3 st/site, respectively) before seroconversion. Compared to non-seroconverters (IN and SN; 5.1 × 10−3 st/site and 5.9 × 10−3 st/site, respectively), the sequence diversity of seroconverters (IS and SS; 10.9 × 10−3 st/site and 9.9 × 10−3 st/site, respectively) was significantly higher after seroconversion ( p < 0.05), and was higher in seroconverters after seroconversion than before seroconversion ( p < 0.05), while this changed very little in non-seroconverters during the observation period. Phylogenetic trees showed greater complexity in secoconverters than non-seroconverters. Parsimony-based estimation of the direction of sequence change between descendants and ancestors before HBeAg seroconversion, revealed higher frequencies of transversional A to T substitution in seroconverters (0.06 vs . 0.02, p = 0.0036) that coincided with the dynamics of quasi-species possessing A1762T mutation. Conclusions The distinctly greater viral diversity in HBeAg seroconverters after seroconversion could be related to escape mutants resulting from stronger selection pressure.