title: Supportive role played by precore and preS2 genomic changes in the establishment of lamivudine-resistant hepatitis B virus.
abstract: BACKGROUND
  Hepatitis B virus (HBV) establishes lamivudine resistance via the resistance-causative rtM204V/I mutation and the replication-compensatory rtL180M mutation. However, both lamivudine-resistant viruses with and those without rtL180M can exist in clinical settings. To elucidate the differences between viruses with and those without rtL180M, we conducted full-length sequencing analysis of HBV derived from patients with type B chronic hepatitis showing lamivudine resistance.
  
  
  METHODS
  The full-length HBV DNA sequences derived from 44 patients showing lamivudine resistance were determined by polymerase chain reaction direct sequencing. Viral replicative competence was examined by in vitro transfection analysis using various HBV-expressing plasmids.
  
  
  RESULTS
  Throughout the HBV genome, a precore-defective A1896 mutation and a short deletion in the preS2 gene were detected more frequently in viruses without rtL180M than in those with it (64% vs. 17% [P < .005] and 50% vs. 10% [P < .01], respectively). In vitro transfection analysis revealed that the level of reduction in intracellular viral replication caused by the introduction of lamivudine resistance-associated mutations was lower in precore-defective and preS2-deleted viruses than in wild-type virus.
  
  
  CONCLUSIONS
  Both the precore-defective mutation and the preS2 deletion may play a supportive role in the replication of lamivudine-resistant HBV, which may be a reason for there being no need for the compensatory rtL180M mutation in lamivudine-resistant HBV possessing the precore and preS2 genomic changes.
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Kazuyoshi
authors: K
authors: Ohkawa
authors: Tetsuo
authors: T
authors: Takehara
authors: Michio
authors: M
authors: Kato
authors: Matsuo
authors: M
authors: Deguchi
authors: Masanori
authors: M
authors: Kagita
authors: Hayato
authors: H
authors: Hikita
authors: Akira
authors: A
authors: Sasakawa
authors: Keisuke
authors: K
authors: Kohga
authors: Akio
authors: A
authors: Uemura
authors: Ryotaro
authors: R
authors: Sakamori
authors: Shinjiro
authors: S
authors: Yamaguchi
authors: Takuya
authors: T
authors: Miyagi
authors: Hisashi
authors: H
authors: Ishida
authors: Tomohide
authors: T
authors: Tatsumi
authors: Norio
authors: N
authors: Hayashi
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D016679:Genome, Viral; D006512:Hepatitis B Core Antigens / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; D019259:Lamivudine