Functional analysis of mutations conferring lamivudine resistance on hepatitis B virus

J Gen Virol. 1999 Mar;80 ( Pt 3):601-606. doi: 10.1099/0022-1317-80-3-601.


Two patterns of mutation are commonly observed in the polymerase gene of lamivudine [(-)2'-deoxy-3'-thiacytidine]-resistant hepatitis B virus (HBV). The M539I substitution in the conserved YMDD motif occurs independently of other changes, whereas the M539V substitution is associated with an additional upstream change (L515M). These mutations were introduced into a common background and their effects on HBV DNA replication and lamivudine resistance studied. The L515M and M539V mutations provided only partial resistance while the M539I mutation conferred a high degree of lamivudine resistance. The combination of the L515M and M539V mutations gave an intermediate level of replication competence, compared with either mutation alone, and increased resistance to lamivudine. This probably accounts for these two mutations always being observed together. The M539I mutation reduced replication competence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Blotting, Southern
  • DNA Replication / genetics
  • DNA, Circular / metabolism
  • DNA, Viral / metabolism
  • Drug Resistance, Microbial
  • Genes, Viral / genetics
  • Hepatitis B virus / drug effects
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / growth & development
  • Humans
  • Lamivudine / pharmacology*
  • Liver Neoplasms / virology
  • Mutation*
  • Polymerase Chain Reaction
  • RNA, Messenger / metabolism
  • RNA-Directed DNA Polymerase / genetics*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Transfection
  • Tumor Cells, Cultured


  • Antiviral Agents
  • DNA, Circular
  • DNA, Viral
  • RNA, Messenger
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • RNA-Directed DNA Polymerase