Membrane fusion mediated by herpesvirus glycoproteins: the paradigm of varicella‐zoster virus

Abstract

Varicella-zoster virus (VZV) is well known for its propensity to cause polykaryons (syncytia) in the vesicles within infected skin. Similarly in cultured cells, VZV induces extensive syncytial formation by virus-mediated cell-to-cell fusion. Statistical analyses of fusion parameters demonstrated three-way interactive effects among all three tested variables (incubation temperature, cell type and virus strain). For example, fusion was greatly enhanced at 33 degrees C vs 37 degrees C; also fusion was pronounced in epidermal cells but negligible in fibroblast cells. As with all herpesviruses, VZV gH was a major fusogen. VZV cell fusion was inhibited by antibody to gH, but surprisingly was enhanced by antibody to gE. Other evidence implicating a role for VZV gE in the fusion process was provided by two mutant viruses, in which gE cell surface expression was enhanced. Under transfection conditions, VZV fusion formation occurred after expression of the gH/gL complex; in contrast, pseudorabies virus requires expression of gH, gL and gB, while the herpes simplex virus (HSV) types 1 and 2 require the quartet of gH, gL, gB and gD. VZV has no gD gene and no apparent gD functional homologue. On the other hand, VZV gE exerts a greater effect than HSV gE on membrane fusion. Taken together, the data in this review suggest that VZV has evolved viral glycoprotein machinery more geared toward cell-to-cell fusion (fusion-from-within) than toward virus-to-cell fusion (entry/fusion-from-without), as a means for syncytium formation within the human epidermis.

Human Anti-Varicella-Zoster Virus (VZV) Recombinant Monoclonal Antibody Produced after Zostavax Immunization Recognizes the gH/gL Complex and Neutralizes VZV Infection

“…Monoclonal antibodies against conformation-dependent VZV gH epitopes have been shown to neutralize VZV (3,11), as did our rec-RC IgG antibody. Importantly, gH and possibly gL are present in cell surface areas of "viral highways" and may be involved in cell-to-cell spread of VZV (5).…”

“…Along with membrane fusion, VZV gH and gL are also involved in virus egress and are essential for virus replication (1)(2)(3)(4). In addition to mediating virus entry, VZV glycoproteins can traffic from infected cells to uninfected cells (5). VZV glycoproteins induce strong humoral immune responses both in naturally infected individuals and in varicella or zoster vaccine recipients (6)(7)(8)(9)(10).…”

“…While VZV gE is the most immunogenic and predominant glycoprotein in VZV-infected cell membranes, antibodies to VZV gH are the major neutralizing antibodies (11-16). It is likely that neutralizing activity by the gH/gL complex effectively prevents cell-to-cell virus spread (5,(17)(18)(19)(20).Analysis of VZV attachment and membrane fusion requires highly specific neutralizing antibodies. Hybridoma cell lines and phage display libraries produce human anti-VZV gE and gH monoclonal antibodies (MAbs) that neutralize virus infection (21-24).…”

Virion-Incorporated Glycoprotein B Mediates Transneuronal Spread of Pseudorabies Virus

“…Recent immunoelectron microscopy studies by Miranda-Saksena et al reveal that the neurosecretion proteins SNAP-25, Rab3A, and GAP-43 are associated with HSV-1 virions in the axons of human fetal dorsal root ganglia (31). Syncytium formation occurs in various cell types upon infection by alphaherpesviruses and depends on cell surface expression of viral fusion proteins (8,46). Membrane dye transfer and electrophysiology experiments suggest that transient or permanent membrane and cytoplasmic continuity may exist between an infected neuron and the cell it contacts (5; McCarthy et al, unpublished).…”

Fusogenic Domains in Herpes Simplex Virus Type 1 Glycoprotein H

“…Unlike orthomyxoviruses, paramyxoviruses, filoviruses, and retroviruses, which use a single glycoprotein for membrane fusion, herpesviruses employ multicomponent membrane fusion machines that comprise at least three proteins, glycoprotein B (gB), glycoprotein H (gH), and glycoprotein L (gL), all of which are conserved in all members of the Herpesviridae family. In addition to this core requirement for fusion (as exemplified by a number of reports on different members of the herpesvirus family (34,35)), other glycoproteins may also be involved. For example, herpes simplex virus type 1 (HSV-1)-mediated fusion requires gB, gH, gL, and glycoprotein D (36 -38), whereas fusion of the ␥-herpesvirus (Epstein-Barr virus) is mediated by gB, gH, gL, and gp42 (39 -41).…”