The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound.
The hepatitis B virus (HBV) mutation that encodes rtA181T is selected in the viral polymerase during antiviral drug therapy and can also encode a stop codon in the overlapping surface gene at amino acid 172 (sW172*) resulting in truncation of the last 55 amino acids of the C-terminal hydrophobic region of the surface proteins. This mutation is usually detected as a mixed population with wild-type HBV. In vitro analysis revealed that the rtA181T/sW172* variant is not only defective in secretion of viral particles causing intracellular retention of surface proteins, it also has a dominant negative effect on virion but not subviral particle secretion when coexpressed with the wild type. This dominant negative effect was attributed to the truncated S protein alone. Furthermore, these truncated surface proteins were less glycosylated, and the truncated L protein was able to support virion secretion. Examination of sequential HBV DNA levels in patients failing lamivudine or adefovir therapy where only the rtA181T change was detected via polymerase chain reaction sequencing revealed that viral load rebound did not occur or was not as large as usually observed with drug-resistant HBV.


CONCLUSIONS
The rtA181T/sW172* variant has a secretory defect and exerts a dominant negative effect on wild-type HBV virion secretion. The selection of rtA181T/sW172* reduced the typical extent of virological breakthrough, resulting in a missed diagnosis of drug resistance if viral load was used as the only criterion for drug failure, necessitating HBV polymerase chain reaction sequencing or other genotypic methods to diagnose antiviral drug resistance in these cases.
Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia.
Nadia
N
Warner
Stephen
S
Locarnini
D000409:Alanine; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018388:Codon, Terminator; D004261:DNA Replication; D005799:Genes, Dominant; D006031:Glycosylation; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D009154:Mutation; D012194:RNA-Directed DNA Polymerase; D013912:Threonine; D014018:Tissue Distribution; D014162:Transfection; D019562:Viral Load; D014771:Virion / Q000648:ultrastructure; D014779:Virus Replication / Q000235:genetics
D000998:Antiviral Agents; D018388:Codon, Terminator; D008565:Membrane Proteins; D013912:Threonine; D012194:RNA-Directed DNA Polymerase; D000409:Alanine