title: Convergence and coevolution of hepatitis B virus drug resistance.
abstract: Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance.
authors.affiliation: Molecular Epidemiology and Bioinformatics Laboratory, Division of Viral Hepatitis, Center for Disease Control and Prevention, Atlanta 30329, Georgia, USA. guy8@cdc.gov
authors.forename: Hong
authors.initials: H
authors.lastname: Thai
authors.forename: David S
authors.initials: DS
authors.lastname: Campo
authors.forename: James
authors.initials: J
authors.lastname: Lara
authors.forename: Zoya
authors.initials: Z
authors.lastname: Dimitrova
authors.forename: Sumathi
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xia
authors.forename: Lilia
authors.initials: L
authors.lastname: Ganova-Raeva
authors.forename: Chong-Gee
authors.initials: CG
authors.lastname: Teo
authors.forename: Anna
authors.initials: A
authors.lastname: Lok
authors.forename: Yury
authors.initials: Y
authors.lastname: Khudyakov
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D002648:Child; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D016679:Genome, Viral; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase