title: A double mutation in glycoprotein gB compensates for ineffective gD-dependent initiation of herpes simplex virus type 1 infection.
abstract: Herpes simplex virus (HSV) entry into cells is triggered by the binding of envelope glycoprotein D (gD) to a specific receptor, such as nectin-1 or herpesvirus entry mediator (HVEM), resulting in activation of the fusion effectors gB and gH and virus penetration. Here we report the identification of a hyperactive gB allele, D285N/A549T, selected by repeat passage of a gD mutant virus defective for nectin-1 binding through cells that express a gD-binding-impaired mutant nectin-1. The gB allele in a wild-type virus background enabled the use of other nectins as virus entry receptors. In addition, combination of the mutant allele with an epidermal growth factor receptor (EGFR)-retargeted gD gene yielded dramatically increased EGFR-specific virus entry compared to retargeted virus carrying wild-type gB. Entry of the gB mutant virus into nectin-1-bearing cells was markedly accelerated compared to that of wild-type virus, suggesting that the gB mutations affect a rate-limiting step in entry. Our observations indicate that ineffective gD activation can be complemented by hypersensitization of a downstream component of the entry cascade to gD signaling.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Uchida
authors.forename: Janet
authors.initials: J
authors.lastname: Chan
authors.forename: William F
authors.initials: WF
authors.lastname: Goins
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.forename: Izumi
authors.initials: I
authors.lastname: Kumagai
authors.forename: Justus B
authors.initials: JB
authors.lastname: Cohen
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso
mesh_terms: D000818:Animals; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006561:Herpes Simplex / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D000075983:Nectins; D011991:Receptors, Virus / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D053586:Virus Internalization
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; C039447:glycoprotein D, Human herpesvirus 1; D066246:ErbB Receptors