HERPES-SIMPLEX VIRUS GLYCOPROTEIN-D CAN BIND TO POLIOVIRUS RECEPTOR-RELATED PROTEIN-1 OR HERPESVIRUS ENTRY MEDIATOR, 2 STRUCTURALLY UNRELATED MEDIATORS OF VIRUS ENTRY

Several cell membrane proteins have been identified as herpes simplex virus (HSV) entry mediators (Hve). HveA (formerly HVEM) is a member of the tumor necrosis factor receptor family, whereas the poliovirus rec eptor-related proteins 1 and 2 (PRR1 and PRR2, renamed HveC and HveB) belong to the immunoglobulin superfamily. Here we show that a truncate d form of HveC directly binds to HSV glycoprotein D (gD) in solution a nd at the surface of virions. This interaction is dependent on the nat ive conformation of go but independent of its N-linked glycosylation. Complex formation between soluble go and HveC appears to involve one o r two go molecules for one HveC protein. Since HveA also mediates HSV entry by interacting with go, we compared both structurally unrelated receptors for their binding to go. Analyses of several go variants ind icated that structure and accessibility of the N-terminal domain of go , essential for HveA binding, was not necessary for HveC interaction. Mutations in functional regions II, III, and IV of go had similar effe cts on binding to either HveC or HveA. Competition assays with neutral izing anti-go monoclonal antibodies (MAbs) showed that MAbs from group Tt, prevented HveC and HveA binding to virions. However, group Ia MAb s blocked HveC but not HveA binding, and conversely, group VII MAbs bl ocked HveA but not HveC binding. Thus, we propose that HSV entry can b e mediated by two structurally unrelated go receptors through related but not identical binding with gD.