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Review
. 2003 Oct;77(19):10179-85.
doi: 10.1128/jvi.77.19.10179-10185.2003.

Herpesvirus entry: an update

Patricia G Spear  1 , Richard Longnecker
Affiliations
Review

Herpesvirus entry: an update

Patricia G Spear et al. J Virol. 2003 Oct.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Participants in herpesvirus entry and virus-induced cell fusion. For both alphaherpesviruses and gammaherpesviruses, binding to cells can be mediated by a virion glycoprotein that is not essential for entry. The binding receptors are heparan sulfate for HSV gC and HHV-8 K8.1A and CD21 for EBV gp350 (in the case of B cells). Entry requires interaction of a viral ligand with another cell surface receptor. For HSV, virion gD is the ligand for several cell surface receptors (HVEM, nectins, 3-O-sulfated heparan sulfate), any one of which can mediate entry. For EBV entry into B cells, gp42 binds to HLA class II molecules. It should be noted that gp42 is not required for EBV infection of epithelial cells. The entry receptors in epithelial cells have not yet been identified but could include integrins. The viral ligands could be gH and/or BMRF2. For HHV-8 entry, gB can bind to one of the integrins. Any one of these interactions of a viral ligand with an entry receptor is thought to activate the fusion activity of gB and gH-gL.
FIG. 2.
FIG. 2.
Mutational analysis of HSV and EBV entry receptors and ligands. (A) Mutations in HSV gD that influence functional interactions of gD with the various entry receptors. The features of HSV-1 gD (left; in color) and HVEM (right; in gray) shown are based on the crystal structure of gD-HVEM complexes (6). The peptide backbone of gD is shown as a tube in light blue with the beta strands and alpha-helices shown in gold and green, respectively. The peptide backbone of HVEM is shown as a wire in gray with the disulfide bonds in orange. Amino acids 7 to 15 and 24 to 32, the contact regions with HVEM, are shown in black; deletion of one or both of these regions significantly reduces the number of functional interactions of HSV-1 or HSV-2 gD with all known entry-fusion receptors except nectin-1 (48). The amino acid substitutions shown in red (Q27P/R and L25P) enhance functional interactions of HSV-1 gD with nectin-2 but do not have this effect in HSV-2 gD since the latter already has significant activity with nectin-2. The substitution Q27P/R significantly reduces functional interactions of either HSV-1 or HSV-2 gD with HVEM, whereas L25P has much less effect. However, both substitutions reduce the activity of HSV-1 gD with 3-O-sulfated heparan sulfate. The substitutions shown in dark blue represent the amino acid differences found in HSV-2 gD within the first 66 amino acids. These amino acid differences are principally responsible for the greater activity of HSV-2 gD with nectin-2 (49). Thus, the combination of these amino acid substitutions or either of two single amino acid substitutions (Q27P/R or L25P) can render HSV-1 gD more active with nectin-2. (B) Mutations in an HLA class II molecule that influence interactions of gp42 with HLA class II molecules. The structure of gp42 (green) bound to an HLA class II molecule, based on X-ray crystallography of the complex (30), is shown in side view (left) or from above (right). The HLA class II α chain (purple) and β chain (blue) are illustrated, with bound peptide (brown). The residues E46 and R72 (red labels) within HLA DRβ, which areessential for gp42 binding and EBV entry, are indicated by arrows (24). K65 (blue label) mutations can have differential effects on gp42 binding and EBV entry. When the residue is changed to alanine, there is little effect on gp42 binding and EBV entry, whereas mutation to glutamic acid completely abolishes gp42 binding and EBV entry. K65 and R72 are within the alpha helix of the β chain that forms one side of the peptide-binding groove. E46 is within a loop of the β chain that extends from the base of the peptide-binding groove. The hydrophobic pocket of gp42, consisting of I159, V184, Y185, I187, F188, Y194, F198, V201, F210, and L211, is labeled and highlighted.
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