The role of glycoproteins gE and gI in herpes simplex virus cell-to-cell spread

Abstract

<p>Herpes simplex viruses (HSV) infect and spread through the mucosal and submucosal epithelium and can establish a latent infection in the peripheral nervous system. Under appropriate conditions, HSV may reactivate from the latent state, producing secondary disease near the site of the primary infection. A family of HSV encoded glycoproteins found within the virion envelope regulate and promote entry and spread of virus between susceptible cells. I have shown that a complex of the HSV glycoproteins E and I, were required for cell-to-cell spread of HSV across cellular junctions in vivo in vitro, in a manner resistant to anti-HSV antibody neutralization. HSV gE⁻ and gI⁻ mutant viruses spread poorly in the corneal epithelium of mice and rabbits when compared to wild type HSV, and mutant viruses failed to spread to the brain and cause encephalitis. gE and gI were not required for entry of extracellular virus. Both gE⁻ and gI⁻ mutants produced similar yields of HSV compared to wild type HSV following a single round of viral replication, but when forced to spread to neighbouring cells, viral yields were 10-100 fold lower than wild type virus. These data suggest that HSV gE⁻ and gI⁻ mutant unable to efficiently spread from cell-to-cell, and that the gE/gI complex facilitates transfer of HSV across cellular junctions. Since HSV infects neurons and apparently spreads across synaptic junctions, it was of interest to determine whether gE/gI were also important for transneuronal transfer of HSV. gE⁻ and gI⁻ mutant viruses were markedly restricted in their ability to spread within the retina and to the major retinorecipient regions of the brain following injection into the vitreous body of the rat eye. In contrast, wild type virus spread rapidly and infected the majority of the neurons within the retina, and efficiently infected neurons within the brain. Together, these results demonstrated that gE/gI plays a significant role in promoting spread of HSV between cells. To determine the molecular mechanism of how gE/gI facilitates cell-to-cell transmission of HSV, I examined the subcellular distribution of gE/gI in polarized human epithelial cells. Transport of gE to the cell surface required the coexpression of gI. At the surface of polarized cells, gE/gI accumulated along the lateral plasma membrane, with little or no gE/gI on the apical or basal plasma membrane domains. When gE/gI was expressed in subconfluent epithelial monolayers, gE/gI was found only at junctions between cells and not on those lateral surfaces not in contact with another cell. Together, these data support a model in which the gE/gI complex accumulates at cell junctions, perhaps by interacting with junctional components, and in so doing, mediates transfer of HSV across cell junctions.</p>