Complementation of Wild-Type and Drug-Resistant Hepatitis B Virus Genomes to Maintain Viral Replication and Rescue Virion Production under Nucleos(t)ide Analogs

Virol Sin. 2019 Aug;34(4):377-385. doi: 10.1007/s12250-019-00143-y. Epub 2019 Jun 19.

Abstract

As the open reading frames of hepatitis B virus (HBV) genomes are overlapping, resistance mutations (MTs) in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins, which are usually detected as a mixed population with wild-type (WT) HBV. The question was raised how the coexistence of nucleos(t)ide analogs (NAs) resistance MTs and WT sequences affects HBV replication. In the present study, HBV genomes with frequently detected reverse transcriptase (RT)/surface truncation MTs, rtA181T/sW172*, rtV191I/sW182* and rtM204I/sW196*, were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of NAs. In the absence of NAs, RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins, and had a dose-dependent negative effect on WT HBV virion secretion. However, in the presence of NAs, coexistence of MTs with WT maintained viral replication, and the presence of WT was able to rescue the production of MT HBV virions. Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.

Keywords: Hepatitis B virus (HBV); Nucleos(t)ide analogs resistance mutations; Surface truncation mutation; Viral replication.

MeSH terms

  • Antiviral Agents / pharmacology
  • Drug Resistance, Viral / genetics
  • Genetic Complementation Test
  • Genome, Viral*
  • Hepatitis B / virology
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / enzymology
  • Hepatitis B virus / genetics*
  • Humans
  • Mutation
  • Nucleosides / pharmacology*
  • RNA-Directed DNA Polymerase / genetics
  • Virion / drug effects
  • Virion / genetics*
  • Virus Replication*

Substances

  • Antiviral Agents
  • Nucleosides
  • RNA-Directed DNA Polymerase