title: Antibody-induced conformational changes in herpes simplex virus glycoprotein gD reveal new targets for virus neutralization.
abstract: As the receptor-binding protein of herpes simplex virus (HSV), gD plays an essential role in virus entry. In its native state, the last 56 amino acids of the ectodomain C terminus (C-term) occlude binding to its receptors, herpesvirus entry mediator (HVEM) and nectin-1. Although it is clear that movement of the C-term must occur to permit receptor binding, we believe that this conformational change is also a key event for triggering later steps leading to fusion. Specifically, gD mutants containing disulfide bonds that constrain the C-term are deficient in their ability to trigger fusion following receptor binding. In this report, we show that two newly made monoclonal antibodies (MAbs), MC2 and MC5, have virus-neutralizing activity but do not block binding of gD to either receptor. In contrast, all previously characterized neutralizing anti-gD MAbs block binding of gD to a receptor(s). Interestingly, instead of blocking receptor binding, MC2 significantly enhances the affinity of gD for both receptors. Several nonneutralizing MAbs (MC4, MC10, and MC14) also enhanced gD-receptor binding. While MC2 and MC5 recognized different epitopes on the core of gD, these nonneutralizing MAbs recognized the gD C-term. Both the neutralizing capacity and rate of neutralization of virus by MC2 are uniquely enhanced when MC2 is combined with MAb MC4, MC10, or MC14. We suggest that MC2 and MC5 prevent gD from performing a function that triggers later steps leading to fusion and that the epitope for MC2 is normally occluded by the C-term of the gD ectodomain.
authors: Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Eric
authors: E
authors: Lazear
authors: J Charles
authors: JC
authors: Whitbeck
authors: Manuel
authors: M
authors: Ponce-de-Leon
authors: Tina M
authors: TM
authors: Cairns
authors: Sharon H
authors: SH
authors: Willis
authors: Yi
authors: Y
authors: Zuo
authors: Claude
authors: C
authors: Krummenacher
authors: Gary H
authors: GH
authors: Cohen
authors: Roselyn J
authors: RJ
authors: Eisenberg
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D015374:Biosensing Techniques; D015153:Blotting, Western; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D009500:Neutralization Tests; D011487:Protein Conformation; D018139:Simplexvirus / Q000737:chemistry / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal