title: Glycoprotein L sets the neutralization profile of murid herpesvirus 4.
abstract: Antibodies readily neutralize acute, epidemic viruses, but are less effective against more indolent pathogens such as herpesviruses. Murid herpesvirus 4 (MuHV-4) provides an accessible model for tracking the fate of antibody-exposed gammaherpesvirus virions. Glycoprotein L (gL) plays a central role in MuHV-4 entry: it allows gH to bind heparan sulfate and regulates fusion-associated conformation changes in gH and gB. However, gL is non-essential: heparan sulfate binding can also occur via gp70, and the gB-gH complex alone seems to be sufficient for membrane fusion. Here, we investigated how gL affects the susceptibility of MuHV-4 to neutralization. Immune sera neutralized gL(-) virions more readily than gL(+) virions, chiefly because heparan sulfate binding now depended on gp70 and was therefore easier to block. However, there were also post-binding effects. First, the downstream, gL-independent conformation of gH became a neutralization target; gL normally prevents this by holding gH in an antigenically distinct heterodimer until after endocytosis. Second, gL(-) virions were more vulnerable to gB-directed neutralization. This covered multiple epitopes and thus seemed to reflect a general opening up of the gH-gB entry complex, which gL again normally restricts to late endosomes. gL therefore limits MuHV-4 neutralization by providing redundancy in cell binding and by keeping key elements of the virion fusion machinery hidden until after endocytosis.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gillet
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Alenquer
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Glauser
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Susanna
authors.initials: S
authors.lastname: Colaco
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Janet S
authors.initials: JS
authors.lastname: May
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004847:Epithelial Cells; D005260:Female; D005347:Fibroblasts; D006023:Glycoproteins / Q000276:immunology*; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D018144:Rhadinovirus / Q000276:immunology* / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D006023:Glycoproteins; D014759:Viral Envelope Proteins