Viral quasi-species evolution during hepatitis Be antigen seroconversion.


Journal Article

BACKGROUND & AIMS: Although viral quasi-species evolution may be related to pathogenesis of disease, little is known about this in hepatitis B virus (HBV); consequently, we aimed to evaluate the evolution of HBV quasi-species in patients with well-characterized clinical phenotypes of chronic hepatitis B. METHODS: Four cohorts of well-defined clinical phenotypes of chronic hepatitis B, hepatitis Be antigen (HBeAg) seroconverters (spontaneous seroconverters and interferon-induced seroconverters) and nonseroconverters (controls and interferon nonresponders) were followed during 60 months on average. Serum from 4 to 5 time points was used for nested polymerase chain reaction, cloning, and sequencing of the precore/core gene (20 clones/sample). Only patients with genotype B were used. Sequences were aligned using Clustal X, then serial-sample unweighted pair grouping method with arithmetic means phylogenetic trees were constructed using Pebble 1.0 after which maximum likelihood estimates of pairwise distances under a GTR + I + G model was assessed. Viral diversity and substitution rates were then estimated. RESULTS: Analysis of 3386 sequences showed that HBeAg seroconverters had 2.4-fold higher preseroconversion viral sequence diversity (P = .0183), and 10-fold higher substitution rate (P < .0001) than did nonseroconverters, who had persistently low viral diversity (3.6 x 10(-3) substitutions/site) and substitution rate (2.2 x 10(-5) substitutions x site(-1) x month(-1)). After seroconversion, there was a striking increase in viral diversity. Most seroconverters had viral variants that showed evidence of positive selection, which was seen mainly after seroconversion. CONCLUSIONS: The high viral diversity before a reduction in HBV DNA and before HBeAg seroconversion could either be related to occurrence of stochastic mutations that lead to a break in immune tolerance or to increased immune reactivity that drives escape mutations.

Full Text

Cited Authors

  • Lim, SG; Cheng, Y; Guindon, S; Seet, BL; Lee, LY; Hu, P; Wasser, S; Peter, FJ; Tan, T; Goode, M; Rodrigo, AG

Published Date

  • September 2007

Published In

Volume / Issue

  • 133 / 3

Start / End Page

  • 951 - 958

PubMed ID

  • 17854598

Pubmed Central ID

  • 17854598

Electronic International Standard Serial Number (EISSN)

  • 1528-0012

International Standard Serial Number (ISSN)

  • 0016-5085

Digital Object Identifier (DOI)

  • 10.1053/j.gastro.2007.06.011


  • eng