Hepatitis B virus mutations associated with antiviral therapy.
The hepatitis B virus (HBV) replicates via an error prone viral reverse transcriptase resulting in a large pool of quasispecies with mutations spread throughout the genome. During antiviral drug selection pressure (e.g., lamivudine, adefovir, or entecavir) HBV mutants are selected from the pre-existing pool of quasispecies and over time become the dominant species. Not all mutations result in replication competent virus as HBV has the added complexity of overlapping reading frames. The HBV polymerase (Pol) gene overlaps the hepatitis B surface antigen (HBsAg) in a frame-shifted manner with the result that drug-resistant mutations in the HBV Pol can directly impact on the nature of HBsAg and its function. HBV genomic databases have been established to monitor antiviral selected mutations and are useful in determining conserved residues, genotypic differences, polymorphisms, and the mutation profiles selected under different antiviral selection pressures. These HBV databases may aid in the development of new diagnostic reagents as well as the monitoring of polymerase and envelope mutations selected under different antiviral pressures. Antiviral drug resistant mutants emerge as a function of at least six factors: the viral mutation frequency, the intrinsic mutability of the antiviral target site, the selective pressure exerted by the drug, the magnitude and rate of virus replication, the overall replication fitness of the mutant, and the availability of replication space. Only a limited number of HBsAg mutations selected during antiviral treatment have been characterized and the diagnostic and public health implications of these mutations need further investigation. Clearly, improved treatment strategies are required urgently to prevent the continued selection of HBV drug-resistant mutants.
Bartholomeusz
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Victorian Infectious Disease Reference Laboratory, North Melbourne, Australia. angeline@mh.org.au
Locarnini
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D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015751:Genes, pol / Q000235:genetics; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000187:drug effects*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics
D000998:Antiviral Agents; D014759:Viral Envelope Proteins; D012194:RNA-Directed DNA Polymerase