title: Discrimination between sialic acid-containing receptors and pseudoreceptors regulates polyomavirus spread in the mouse.
abstract: Variations in the polyomavirus major capsid protein VP1 underlie important biological differences between highly pathogenic large-plaque and relatively nonpathogenic small-plaque strains. These polymorphisms constitute major determinants of virus spread in mice and also dictate previously recognized strain differences in sialyloligosaccharide binding. X-ray crystallographic studies have shown that these determinants affect binding to the sialic acids. Here we report results of further experiments designed to test the importance of specific contacts between VP1 and the carbohydrate moieties of the receptor. With minor exceptions, substitutions at positions predicted from crystallography to be important in binding the terminal alpha-2,3-linked sialic acid or the penultimate sugar (galactose) destroyed the ability of the virus to replicate in cell culture. Substitutions that prevented binding to a branched disialyloligosaccharide were found to result in viruses that were both viable in culture and tumorigenic in the mouse. Conversely, substitutions that allowed recognition and binding of the branched carbohydrate chain inhibited spread in the mouse, though the viruses remained viable in culture. Mice of five different inbred strains, all highly susceptible to large-plaque virus, showed resistance to the spread of polyomavirus strains bearing the VP1 type which binds the branched-chain receptor. We suggest that glycoproteins bearing the appropriate O-linked branched sialyloligosaccharide chains are effective pseudoreceptors in the host and that they block the spread of potentially tumorigenic or virulent virus strains.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Bauer
authors.forename: C
authors.initials: C
authors.lastname: Cui
authors.forename: W R
authors.initials: WR
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Stehle
authors.forename: S C
authors.initials: SC
authors.lastname: Harrison
authors.forename: J A
authors.initials: JA
authors.lastname: DeCaprio
authors.forename: T L
authors.initials: TL
authors.lastname: Benjamin
mesh_terms: D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D002213:Capsid / Q000378:metabolism*; D036022:Capsid Proteins; D006224:Cricetinae; D018698:Glutamic Acid; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D011120:Polyomavirus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D027601:Polyomavirus Infections / Q000473:pathology / Q000821:virology; D011991:Receptors, Virus / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology; D014774:Virulence
chemical_list: D036022:Capsid Proteins; D011991:Receptors, Virus; D012795:Sialoglycoproteins; C062481:VP1 protein, polyomavirus; D018698:Glutamic Acid; D019158:N-Acetylneuraminic Acid