Identification of a novel pre-S2 mutation in a subgroup of chronic carriers with spontaneous clearance of hepatitis B virus surface antigen

J Gastroenterol Hepatol. 2003 Oct;18(10):1129-38. doi: 10.1046/j.1440-1746.2003.03146.x.


Background and aim: The aim of the present study was to investigate whether spontaneous seroclearance of hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B could be attributed to the presence of pre-S/S gene mutations.

Methods: Of 34 hepatitis B virus (HBV) carriers who experienced spontaneous seroclearance of HBsAg, 30 were still seropositive for HBV DNA. The serum samples of these carriers were subjected to sequence analysis.

Results: A novel pre-S2 mutation, G149R, was found in nine (group I) but not in 17 (group II) patients carrying HBV DNA with intact pre-S/S reading frames. In the remaining four patients (group III), only aberrant pre-S/S transcripts were found in their sera. Distinct patterns of amino acid substitutions specific to group I and II patients were identified. Superinfection by hepatitis C or D virus occurred predominantly in group II patients (P = 0.019). Superinfection by HBV of a different genotype occurred predominantly in patients without hepatitis C or D virus superinfection (P = 0.013). Site-directed mutagenesis experiments showed that secretion of HBsAg was not defective in the pre-S2 G149R mutant.

Conclusions: In a particular subgroup (group I) of patients, seroclearance of HBsAg was not caused by superinfection of other hepatitis viruses, nor was it caused by failure of HBsAg secretion or detection. Instead, a yet unrecognized mechanism associated with emergence of a novel pre-S2 mutation is responsible.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution
  • Carrier State / virology*
  • DNA, Viral / genetics
  • Female
  • Genotype
  • Hepatitis B Surface Antigens / blood*
  • Hepatitis B Surface Antigens / genetics*
  • Hepatitis B virus / genetics
  • Hepatitis B, Chronic / virology*
  • Humans
  • Male
  • Middle Aged
  • Mutagenesis, Site-Directed
  • Mutation*
  • Protein Precursors / genetics*
  • Reading Frames
  • Sequence Analysis, Protein
  • Superinfection / virology


  • DNA, Viral
  • Hepatitis B Surface Antigens
  • Protein Precursors
  • presurface protein 2, hepatitis B surface antigen