title: Stop codons in the hepatitis B surface proteins are enriched during antiviral therapy and are associated with host cell apoptosis.
abstract: Premature stop codons in the hepatitis B virus (HBV) surface protein can be associated with nucleos(t)ide analogue resistance due to overlap of the HBV surface and polymerase genes. The aim of this study was to determine the effect of the replication of three common surface stop codon variants on the hepatocyte. Cell lines were transfected with infectious HBV clones encoding surface stop codons rtM204I/sW196*, rtA181T/sW172*, rtV191I/sW182*, and a panel of substitutions in the surface proteins. HBsAg was measured by Western blotting. Proliferation and apoptosis were measured using flow cytometry. All three surface stop codon variants were defective in HBsAg secretion. Cells transfected with these variants were less proliferative and had higher levels of apoptosis than those transfected with variants that did not encode surface stop codons. The most cytopathic variant was rtM204I/sW196*. Replication of HBV encoding surface stop codons was toxic to the cell and promoted apoptosis, exacerbating disease progression.
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Colledge
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Soppe
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia.
authors.forename: Lilly
authors.initials: L
authors.lastname: Yuen
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia.
authors.forename: Lucy
authors.initials: L
authors.lastname: Selleck
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia.
authors.forename: Renae
authors.initials: R
authors.lastname: Walsh
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia. Electronic address: stephen.locarnini@mh.org.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
authors.affiliation: Molecular Research and Development, Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Warner
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D017209:Apoptosis; D018388:Codon, Terminator / Q000235:genetics*; D006509:Hepatitis B / Q000188:drug therapy / Q000503:physiopathology* / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D018388:Codon, Terminator; D006514:Hepatitis B Surface Antigens
keywords: Apoptosis; Cytopathic variant; Hepatitis B virus; Nucleos(t)ide analogue resistance; Pathogenic variants; Surface stop codons