PVRL1 is a Ca2+-independent homophilic cell adhesion molecule that belongs to the immunoglobulin superfamily. Human PVRL1 is identical to the poliovirus receptor-related protein (PRR) and is identified to be the alphaherpesvirus entry mediator. PVRL1 constitutes a family consisting of at least PVRL1 1, 2 and 3. PVRL1 2 and 3 are ubiquitously expressed, whereas PVRL1 1 is abundantly expressed in the brain. PVRL1 1 exists as PVRL1 1(alpha) and 1(beta)/HIgR, produced by alternative splicing. The cytoplasmic regions of PVRL1 1(alpha), but not PVRL1 1(beta)/HIgR, have a C-terminal conserved motif (E/A-X-Y-V). This motif interacts with the PDZ domain of the F-Actin-binding protein, afadin, through which it is linked to the Actin cytoskeleton. PVRL1 1, also designated HveC/ PRR1, allows the entry of herpes simplex virus type 1 (HSV-1) and HSV-2 into mammalian cells. The interaction of virus envelope glycoprotein D (gD) with PVRL1 1 is an essential step in the process leading to membrane fusion; the gD binding site is located at the first Ig-like domain of PVRL1 1. Both the transinteraction of PVRL1 and the interaction of PVRL1 with afadin are necessary for their co-localization with E-cadherin and catenins at adherens junctions.