title: Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients.
abstract: The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10-5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses.
authors.affiliation: Institute for Integrative Systems Biology (I2SysBio), Universitat de València, València, Spain.
authors.forename: Marianoel
authors.initials: M
authors.lastname: Pereira-Gómez
authors.affiliation: Institute for Integrative Systems Biology (I2SysBio), Universitat de València, València, Spain.
authors.forename: Juan-Vicente
authors.initials: JV
authors.lastname: Bou
authors.affiliation: Institute for Integrative Systems Biology (I2SysBio), Universitat de València, València, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Andreu
authors.affiliation: Institute for Integrative Systems Biology (I2SysBio), Universitat de València, València, Spain.|Departament de Genètica, Universitat de València, València, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sanjuán
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000187:drug effects*; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009154:Mutation / Q000187:drug effects*; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide
chemical_list: D007166:Immunosuppressive Agents; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D000225:Adenine