The V domain of herpesvirus Ig-like receptor (HIgR) contains a major functional region in herpes simplex virus-1 entry into cells and interacts physically with the viral glycoprotein D

The herpesvirus entry mediator C (HveC), previously known as poliovirus rec eptor-related protein 1 (PRR1), and the herpesvirus Ig-like receptor (HIgR) are the bona fide receptors employed by herpes simplex virus-1 and -2 (HSV -1 and -2) for entry into the human cell lines most frequently used in HSV studies. They share an identical ectodomain made of one V and two C2 domain s and differ in transmembrane and cytoplasmic regions. Expression of their mRNA in the human nervous system suggests possible usage of these receptors in humans in the path of neuron infection by HSV, Glycoprotein D (gD) is t he virion component that mediates HSV-1 entry into cells by interaction wit h cellular receptors, We report on the identification of the V domain of HI gR/PRR1 as a major functional region in HSV-I entry by several approaches. First, the epitope recognized by mAb R1.302 to HIgR/PRR1, capable of inhibi ting infection, was mapped to the V domain. Second, a soluble form of HIgR/ PRR1 consisting of the single V domain competed with cell-bound full-length receptor and blocked virion infectivity. Third, the V domain was sufficien t to mediate HSV entry, as an engineered form of PRR1 in which the two C2 d omains were deleted and the V domain was retained and fused to its transmem brane and cytoplasmic regions was still able to confer susceptibility, alth ough at reduced efficiency relative to full-length receptor. Consistently, transfer of the V domain of HIgR/PRR1 to a functionally inactive structural homologue generated a chimeric receptor with virus entry activity. Finally , the single V domain was sufficient for in vitro physical interaction with go. The in vitro binding was specific as it was competed both by antibodie s to the receptor and by a mAb to go with potent neutralizing activity for HSV-1 infectivity.