Three classes of cell surface receptors for alphaherpesvirus entry.

Herpesviruses have been classified into three subfam-ilies on the basis of biological characteristics andgenomic analysis. Members of the alphaherpesvirussubfamily are neurotropic, have a short replicative cycle,and, in general, have a broad host range. In addition,they encode a similar set of homologous genes arrangedin similar order. Also, selected proteins of one alphaher-pesvirus may functionally substitute for the homolog ofanother.Human herpes simplex viruses 1 and 2 (HSV-1 andHSV-2), porcine pseudorabies virus (PRV), and bovineherpesvirus 1 (BHV-1) are representative members of thealphaherpesvirus subfamily and are the subject of thisreview. Natural diseases associated with infections bythese viruses are restricted to specific hosts. However,these viruses can infect selected laboratory animals,such as rodents, and all have a relatively broad hostrange for cultured cells, at least for entry. The obviousinferences are that each of these viruses can use multi-ple cell surface receptors for entry or that each canrecognize structural features of receptors conservedamong human and animal species. The evidence sum-marized here shows that both inferences are correct.The usual manifestations of HSV disease are lesionson mucosal epithelium (oral or genital), skin, or cornea;latent infection of neurons in sensory ganglia; and per-haps recurrent lesions at the site of primary infection,due to reactivation of latent virus from the ganglia. En-cephalitis can occur, albeit rarely in children or adults;newborn infants can suffer from severe disseminateddisease. PRV and BHV-1 can cause similar manifesta-tions of disease in pigs and cattle. Thus, important cel-lular targets of infection include cells of the mucosalepithelium and neurons, but are not limited to these celltypes.The focus of this review is cell surface receptors forentry of alphaherpesviruses into cells. The pathway ofentry is via fusion of the virion envelope with a cellmembrane, often the cell plasma membrane. Membranefusion induced by alphaherpesviruses does not requireactivation by low pH but depends upon multiple interac-tions of viral proteins with cell surface components. Fig-ure 1 identifies components of the viral envelope and cellmembrane that govern viral entry and are describedbelow. The information summarized here probably ap-plies to most alphaherpesviruses except for those, suchas varicella-zoster virus, that apparently lack a geneencoding gD, a viral glycoprotein central to the entryprocess for HSV, PRV, and BHV-1. Citations listed at theend are mostly recent publications related to cell recep-tors for these viruses; reviews should be consulted forearlier work.The components of a herpesvirus particle are its DNAcore, icosahedral capsid, tegument (proteins located be-tween the capsid surface and envelope), and envelope,which is a lipid bilayer containing multiple viral mem-brane proteins and glycoproteins.The alphaherpesvirus envelope contains about adozen viral membrane proteins, only five of which havedefined roles in viral entry. For HSV-1, PRV, and BHV-1,binding of virus to cells is mediated principally by gC,although other glycoproteins such as gB and gD cancontribute to stable binding or can substitute for gC inmediating binding. Penetration of virus requires fusion ofthe virion envelope with a cell membrane and dependson the action of gB, gD, gH, and gL. Deletion of the genesfor any one of these four glycoproteins is lethal andresults in production of virions that can bind to cells,provided gC is present, but cannot penetrate. Interest-ingly, deletion of gC is not a lethal mutation, although it