title: Identification of hepatitis B virus rtS117F substitution as a compensatory mutation for rtM204I during lamivudine therapy.
abstract: OBJECTIVE
  The replication defect of hepatitis B virus (HBV) lamivudine-resistant mutants can be restored by the development of compensatory mutations. Such mutations have long been recognized for the rtM204V mutant, while little is known about any compensatory mutation specific to the rtM204I mutant. The aim of this study was to search for previously unrecognized compensatory mutations following development of lamivudine-resistant mutants.
  
  
  METHODS
  Of 83 lamivudine-resistant patients, 49 and 34 patients harboured the rtM204I and rtM204V mutations, respectively. Serial serum samples obtained during the therapeutic course were submitted to sequence analysis. Site-directed mutagenesis experiments were performed to examine the functions of the identified associated mutations.
  
  
  RESULTS
  Of the 49 patients carrying the rtM204I mutation, 5 subsequently developed an rtS117F substitution during the follow-up, whereas 4 harboured an rtN124D substitution prior to the development of the rtM204I mutation. Emergence of the rtS117F mutation was associated with an increase in hepatitis activity, whereas prior existence of the rtN124D mutation was associated with decompensated liver function upon development of the rtM204I mutation. Site-directed mutagenesis experiments showed that the rtS117F mutation by itself did not confer lamivudine resistance but it compensated for replication deficiency of the rtM204I mutant in HepG2 and Mahlavu cells. Additionally, virion and hepatitis B surface antigen secretion of the rtS117F mutant was significantly impaired.
  
  
  CONCLUSIONS
  The rtS117F substitution served as a compensatory mutation for rtM204I. Emergence of the rtS117F mutation in lamivudine-resistant patients carrying rtM204I was associated with increased hepatitis activities. Prior existence of the rtN124D substitution was associated with liver decompensation upon development of the rtM204I mutation.
authors: Liver Research Unit,  Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Keelung,  Taiwan.
authors: Chih-Lang
authors: CL
authors: Lin
authors: Rong-Nan
authors: RN
authors: Chien
authors: Ching-Chih
authors: CC
authors: Hu
authors: Ming-Wei
authors: MW
authors: Lai
authors: Chau-Ting
authors: CT
authors: Yeh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage*; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D019259:Lamivudine