title: Micro-evolution of the hepatitis B virus genome in hepatitis B e-antigen-positive carriers: comparison of genotypes B and C at various immune stages.
abstract: OBJECTIVE
  Patients with hepatitis B virus (HBV) genotype B infection experience hepatitis B e-antigen (HBeAg) seroconversion at an earlier stage than do patients with genotype C infection. Therefore, this study investigated whether the differential phenotypes are related to HBV genomic evolution.
  
  
  METHODS
  Thirty-three HBeAg-positive patients with a mean follow-up of 3.1 years were enrolled: 16 at the immune tolerance stage (group I) and 17 at the immune clearance stage (group II). The evolution rates of paired viral genomes at enrollment and at the final follow-up in the full-length genome (μf), nonoverlapping regions (synonymous [μs] and nonsynonymous [μa]), and overlapping regions (μ) were calculated. The evolution rates were then compared according to serum alanine aminotransferase (ALT) levels and HBV genotype.
  
  
  RESULTS
  The overall μf evolution rate was lower in group I than in group II (1.4 × 10(-5)  ± 3.3 × 10(-5) vs 1.2 × 10(-3)  ± 1.2 × 10(-3) nucleotide substitution/site/year, P < 0.001). We observed similar results for the μs, μa, and μ evolution rates. All evolution parameters were comparable between genotypes B and C. We determined a positive correlation between μa/y and the area under the average ALT time curve in genotype B (R(2)  = 0.6935, P < 0.0001), but not in genotype C (R(2)  = 0.1606, P = 0.124).
  
  
  CONCLUSIONS
  The evolution rate of the HBV genome is higher at the immune clearance stage than at the immune tolerance stage. Host immune selection might play a role in triggering evolution of genotype B.
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.forename: Ting-Chih
authors.initials: TC
authors.lastname: Chen
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Hurng-Yi
authors.initials: HY
authors.lastname: Wang
authors.forename: Tai-Chung
authors.initials: TC
authors.lastname: Tseng
authors.forename: Huei-Ru
authors.initials: HR
authors.lastname: Cheng
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Liu
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D002353:Carrier State; D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D016679:Genome, Viral / Q000235:genetics*; D005838:Genotype; D006509:Hepatitis B / Q000276:immunology* / Q000821:virology*; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008297:Male; D013997:Time Factors; D055815:Young Adult
chemical_list: D006513:Hepatitis B e Antigens; D000410:Alanine Transaminase
keywords: evolution; genome; genotype; hepatitis B virus (HBV)