title: Herpes simplex virus type 2 glycoprotein G is targeted by the sulfated oligo- and polysaccharide inhibitors of virus attachment to cells.
abstract: Variants of herpes simplex virus type 2 (HSV-2) generated by virus passage in GMK-AH1 cells in the presence of the sulfated oligosaccharide PI-88 were analyzed. Many of these variants were substantially resistant to PI-88 in their initial infection of cells and/or their cell-to-cell spread. The major alteration detected in all variants resistant to PI-88 in the initial infection of cells was a frameshift mutation(s) in the glycoprotein G (gG) gene that resulted in the lack of protein expression. Molecular transfer of the altered gG gene into the wild-type background confirmed that the gG-deficient recombinants were resistant to PI-88. In addition to PI-88, all gG-deficient variants of HSV-2 were resistant to the sulfated polysaccharide heparin. The gG-deficient virions were capable of attaching to cells, and this activity was relatively resistant to PI-88. In addition to having a drug-resistant phenotype, the gG-deficient variants were inefficiently released from infected cells. Purified gG bound to heparin and showed the cell-binding activity which was inhibited by PI-88. Many PI-88 variants produced syncytia in cultured cells and contained alterations in gB, including the syncytium-inducing L792P amino acid substitution. Although this phenotype can enhance the lateral spread of HSV in cells, it conferred no virus resistance to PI-88. Some PI-88 variants also contained occasional alterations in gC, gD, gE, gK, and UL24. In conclusion, we found that glycoprotein gG, a mucin-like component of the HSV-2 envelope, was targeted by sulfated oligo- and polysaccharides. This is a novel finding that suggests the involvement of HSV-2 gG in interactions with sulfated polysaccharides, including cell surface glycosaminoglycans.
authors.affiliation: Department of Clinical Virology, Göteborg University, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden.
authors.forename: Beata
authors.initials: B
authors.lastname: Adamiak
authors.forename: Maria
authors.initials: M
authors.lastname: Ekblad
authors.forename: Tomas
authors.initials: T
authors.lastname: Bergström
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
authors.forename: Edward
authors.initials: E
authors.lastname: Trybala
mesh_terms: D000818:Animals; D002460:Cell Line; D024882:Drug Resistance, Viral; D016368:Frameshift Mutation; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000821:virology; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000494:pharmacology*; D011134:Polysaccharides / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D014759:Viral Envelope Proteins / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010948:Viral Plaque Assay
chemical_list: D009844:Oligosaccharides; D011134:Polysaccharides; D014759:Viral Envelope Proteins; C045464:glycoprotein G, herpes simplex virus type 2; C120158:phosphomannopentaose sulfate