Herpes Simplex Virus Glycoprotein B Binds to Cell Surfaces Independently of Heparan Sulfate and Blocks Virus Entry

Abstract

Herpes simplex virus (HSV) is responsible for mucocutaneous lesions, commonly known as cold sores, and genital lesions or herpes genitalis. After primary infection virus resides latent in sensory and autonomic neurons from where it reactivates periodically (66). Among the important steps in infection, attachment and entry have attracted attention as targets for therapeutic treatments and vaccines. Binding and entry are complex biochemical processes involving 5 of the 12 known surface glycoproteins of the virus (59).Current models postulate an initial association of glycoprotein C (gC) and/or gB with cell surface heparan sulfate proteoglycan (HSPG) (56). Following binding, entry requires the interaction of gD with one of its receptors that include herpesvirus entry mediator (HVEM), nectin-1 and nectin-2, and specific sites in heparan sulfate generated by certain 3-O-sulfotransferases (18,38,55). The envelope-fusion mechanism is not solved yet, but this event requires gB, the heterodimer gH/gL, gD, and a gD entry receptor (7,39,48,63).HSV mutants lacking the gC gene exhibit reduced attachment, but the particles are still infectious (22). For that reason, gC is considered a nonessential glycoprotein for entry. Moreover, cells deficient in proteoglycan synthesis are still permissive to HSV (2). On the contrary, a gB null virus cannot penetrate target cells (9). A polylysine (pK) sequence located in the N terminus of gB is responsible for interaction of gB with HSPG. A virus mutant from which the pK coding sequence of gB is deleted is still infectious, although virus binding is reduced (32). Taken together, these data suggest that binding of HSV to HSPG through gC and/or gB is an important yet not essential event for entry. Since gB is essential for entry, this glycoprotein must carry out a function(s) other than binding to HSPG.Various criteria were used to show that gD binds receptors, and these same criteria should apply to demonstrate the existence of a gB receptor(s). HSV entry should be blocked by (i) antibodies to gB, (ii) soluble forms of gB, (iii) antibodies to receptor, and (iv) soluble forms of receptor. A number of monoclonal antibodies (MAbs) for gB have neutralizing activity (24,47,54). However, a soluble form of HSV-2 gB failed to block entry of HSV-1 and HSV-2 (27, 67). In the present study, we found that a soluble truncated form of HSV-1 gB bound saturably to the surface of different cell types, including HSPGdeficient cells Gro2C and Sog9 (2). The key finding was that soluble gB, like gD, efficiently inhibited HSV-1 entry into Gro2C cells in a dose-dependent manner. The results provide evidence for the existence of an entry receptor specific for gB.

HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

“…The gB homologues of HCMV and other herpesviruses contribute to virion attachment onto cells through interactions with heparan sulfate GAGs and may interact with more specific, saturable receptors (32,33). However, in contrast to gH/gL/ UL128-131, gB expression in ARPE-19 cells did not interfere with HCMV infection (Fig.…”

Virus Infection and Lipid Rafts

“…29,30) Binding of HSV to host cells and entry of HSV into host cells are mediated by a complex process involving the essential viral glycoproteins B (gB), gD, gH, and gL and multiple celluar receptor molecules, including the tumor necrosis factor receptor family members nectin-1 and nectin-2, herpesvirus entry mediator, heparan sulfate proteoglycans, and two members of it the mmunoglobulin superfamily. [43][44][45] HSV entry is inhibited by cholesterol-sequestering drugs such as methyl-b-cyclodextrin and nystatin. Moreover, HSV gB has been detected in lipid rafts after virus attachment and during entry.…”

Effects of Herpes Simplex Virus Amplicon Transduction on Murine Dendritic Cells

“…Third, large antigens as well as immunomodulatory molecules can be delivered to DCs concurrently by a single HSV amplicon, because of its inherently high transgene capacity, providing higher flexibility in regulating immune responses (Bowers et al, 2003). Herpes simplex virus (HSV) gains its entry into cells by fusion of viral envelope with the cell surface membrane though a cascade of interactions involving multiple viral glycoproteins and cellular receptors (Bender et al, 2005;Kwon et al, 2006;Spear et al, 2006). It has been demonstrated that DCs interact with HSV in a glycoprotein-dependent and Tolllike receptor-2 (TLR2)-independent manner (Reske et al, 2008).…”