title: Virion endocytosis is a major target for murid herpesvirus-4 neutralization.
abstract: Herpesviruses consistently transmit from immunocompetent carriers, implying that their neutralization is hard to achieve. Murid herpesvirus-4 (MuHV-4) exploits host IgG Fc receptors to bypass blocks to cell binding, and pH-dependent protein conformation changes to unveil its fusion machinery only after endocytosis. Nevertheless, neutralization remains possible by targeting the virion glycoprotein H (gH)-gL heterodimer, and the neutralizing antibody responses of MuHV-4 carriers are improved by boosting with recombinant gH-gL. We analysed here how gH-gL-directed neutralization works. The MuHV-4 gH-gL binds to heparan sulfate. However, most gH-gL-specific neutralizing antibodies did not block this interaction; neither did they act directly on fusion. Instead, they blocked virion endocytosis and transport to the late endosomes, where membrane fusion normally occurs. The poor endocytosis of gH-gL-neutralized virions was recapitulated precisely by virions genetically lacking gL. Therefore, driving virion uptake appears to be an important function of gH-gL that provides a major target for antibody-mediated neutralization.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Glauser
authors.affiliation: Immunology-Vaccinology, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gillet
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D004705:Endocytosis; D006566:Herpesviridae Infections / Q000276:immunology / Q000503:physiopathology* / Q000662:veterinary* / Q000821:virology; D051379:Mice; D009500:Neutralization Tests; D018144:Rhadinovirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D012376:Rodent Diseases / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014771:Virion / Q000235:genetics / Q000276:immunology* / Q000502:physiology
chemical_list: D057134:Antibodies, Neutralizing; D014759:Viral Envelope Proteins; C065527:glycoprotein H, Herpesvirus 4