title: Herpes simplex virus targeting to the EGF receptor by a gD-specific soluble bridging molecule.
abstract: Herpes simplex virus 1 (HSV-1) enters cells via initial binding of envelope glycoproteins (g) C and B to cell-surface glycosaminoglycans (GAGs) and subsequent membrane fusion involving envelope gD, gB, and gH/gL. Current insights suggest that the fusion process is initiated by interaction of gD with a cognate cellular receptor, such as the widely distributed cell adhesion molecule nectin-1. To redirect the tropism of HSV-1, we have generated a soluble adapter protein (P-V528LH) comprising the gD-binding variable domain of nectin-1 fused to a single-chain antibody (528LH) recognizing the EGF receptor. The adapter molecule enabled HSV-1 entry into naturally nonpermissive CHO cells expressing the human EGF receptor, but not into CHO cells lacking the receptor, and entry was not observed when the antibody portion of the adapter was replaced with an antibody of different specificity. Adapter-mediated entry increased with the viral dose and was nearly as efficient as direct viral entry into nectin-1-bearing CHO cells. Entry depended on viral gD and was diminished in the absence of cellular GAGs. These experiments represent the first demonstration that a soluble molecule can direct HSV infection via a new receptor, supporting the possible utility of this approach for HSV retargeting.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakano
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Asano
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
authors.forename: Heechung
authors.initials: H
authors.lastname: Kwon
authors.forename: William F
authors.initials: WF
authors.lastname: Goins
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: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D000075983:Nectins; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D006025:Glycosaminoglycans; C000619010:NECTIN1 protein, human; D000075983:Nectins; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C020341:glucosaminoglycans; C039447:glycoprotein D, Human herpesvirus 1; D066246:ErbB Receptors