Striking Similarity of Murine Nectin-1α to Human Nectin-1α (HveC) in Sequence and Activity as a Glycoprotein D Receptor for Alphaherpesvirus Entry

Abstract

Members of the alphaherpesvirus subfamily exemplified by herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus 1 (BHV-1) and porcine pseudorabies virus (PRV) have a broad host range in cultured cells. They can also infect animal species other than the natural host and cause symptoms similar to those observed in their natural hosts. For these and other reasons, the mouse has been extensively used as an animal model to study various aspects of alphaherpesvirus pathogenesis including pathology, immune responses, latency, and transneuronal spread of infection. Consequently, there is considerable interest in defining the cell receptors for entry of HSV and other alphaherpesviruses into mouse cells as well as into cells of the natural hosts. The studies described here are part of a larger effort to determine whether evolutionarily related or distinct receptors are used by HSV for entry into mouse and human cells. If related receptors are used and these related receptors have similar expression patterns and functions in mice and humans, this strengthens the case for using mouse models of disease to dissect aspects of pathogenesis that depend on the susceptibility of cells to viral entry.Human and animal representatives of the alphaherpesvirus subfamily exhibit common requirements for entry into cells (26,34). The initial interaction of virus with cells involves binding of the virion glycoprotein gC, and in some cases gB, to cell surface glycosaminoglycans, preferentially heparan sulfate. Four envelope glycoproteins, gB, gD, gH, and gL, are required to mediate the fusion between the virion envelope and cell membrane that allows viral penetration. It is believed that interaction between gD and one of its cognate cell surface receptors triggers the process of fusion.Recently four human cell surface proteins have been identified as gD receptors that mediate the entry into cells of one or more of the alphaherpesviruses (13,29,37). One of these proteins is a newly described member of the tumor necrosis factor receptor family, originally designated the herpesvirus entry mediator (HVEM) (29), later designated herpesvirus entry protein A (HveA) (13, 37), and officially named TN-FRSF14. The other three proteins are related members of the immunoglobulin (Ig) superfamily, a subfamily including the poliovirus receptor (CD155) (24) and two proteins that are not receptors for poliovirus but were originally designated poliovirus receptor-related protein 1 (Prr1) (22) and poliovirus receptor-related protein 2 (Prr2) (10). CD155 mediates the entry of PRV and BHV-1 but has no activity for HSV strains (13). Prr2 was identified as an entry receptor for strains of HSV-1 that could not use HVEM for entry, was also found to be an entry receptor for HSV-2 and PRV, and was designated HveB (37). Prr1 was found to serve as an entry receptor for HSV-1, HSV-2, PRV, and BHV-1 and was designated HveC (13). Recently both HveB and HveC were shown to be homophilic cell adhesion molecules that localize to sites of cadherin-based cell j...

Effects of Herpes Simplex Virus on Structure and Function of Nectin-1/HveC

“…1F, H, and I) in a similar way as described previously in transfected L cells (42). Since human and murine nectin-1 are highly conserved and retain an identical afadin-binding site (30,44), it was not surprising to detect an interaction between human nectin-1 and murine afadin. Interestingly, nectin-1 associated with afadin predominantly at cell junctions, whereas most nectin-1 clustered elsewhere on the cell surface did not colocalize with afadin ( Fig.…”

Identification and characterization of two zebrafish nectin‐1 genes that are differentially expressed in the developing eye and brain

“…The gene encoding nectin-1 is highly conserved among various species and has been shown to be more than 90% similar in mouse and human (Menotti et al, 2000;Shukla et al, 2000). A murine nectin-1 probe (Haarr et al, 2001) gave hybridization signals from the retina of the developing zebrafish (data not shown) and adult mouse eye (Fig.…”

“…Nectin-1 (PRR1/HveC/CD111) is one of the cellular receptors for glycoprotein D (gD) of herpes simplex virus (HSV) (Cocchi et al, 1998;Spear et al, 2000). Expression of a functional receptor has been detected in humans (Cocchi et al, 1998;Geraghty et al, 1998), mice (Menotti et al, 2000;Shukla et al, 2000), and pigs (Milne et al, 2001). Glycoprotein D of HSV binds to a region encompassing amino acids 64 to 104 on the variable loop of mouse nectin-1 (Cocchi et al, 2001;Martinez and Spear, 2002).…”

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

“…HSV2-gD27 has point mutations (D215G, R222N, and F223I) in the nectin-1 receptor binding domain of gD that result in impaired infection of neurons (33), which express nectin-1 (20,21) but little to no HVEM (22)(23)(24). The genome stability of HSV2-gD27 is of concern when the virus is grown in cells that express both nectin-1 and HVEM, which could allow viruses with reversion of point mutations or with compensatory mutations to be selected.…”

“…The two principal receptors for HSV, HVEM (also known as HveA, TNFRSF14, LIGHTR, and CD270) and nectin-1 (also known as HveC, PVRL1, and CD111), are differentially expressed on various cell types. Neurons express abundant nectin-1 (20,21) and little to no HVEM (22)(23)(24), while lymphocytes express HVEM (22) and epithelial cells express both HVEM and nectin-1 (25). HSV gD binds to both HVEM and nectin-1, and this step is essential for HSV infection of cells.…”