Herpes simplex virus type 2 glycoprotein E is required for efficient virus spread from epithelial cells to neurons and for targeting viral proteins from the neuron cell body into axons

Abstract

The HSV-2 lifecycle involves virus spread in a circuit from the inoculation site to dorsal root ganglia and return. We evaluated the role of gE-2 in the virus lifecycle by deleting amino acids 124–495 (gE2-del virus). In the mouse retina infection model, gE2-del virus does not spread to nuclei in the brain, indicating a defect in anterograde (pre-synaptic to post-synaptic neurons) and retrograde (post-synaptic to pre-synaptic neurons) spread. Infection of neuronal cells in vitro demonstrates that gE-2 is required for targeting viral proteins from neuron cell bodies into axons, and for efficient virus spread from epithelial cells to axons. The mouse flank model confirms that gE2-del virus is defective in spread from epithelial cells to neurons. Therefore, we defined two steps in the virus lifecycle that involve gE-2, including efficient spread from epithelial cells to axons and targeting viral components from neuron cell bodies into axons.

Live Attenuated Herpes Simplex Virus 2 Glycoprotein E Deletion Mutant as a Vaccine Candidate Defective in Neuronal Spread

“…The reduction in mortality after i.c. inoculation of gE2-del virus likely reflects the marked defect of the mutant strain in cell-to-cell spread (46). Importantly, no deaths were recorded following high-dose i.v.…”

“…The mutant virus does not have a defect in its ability to replicate in neurons; therefore, death following direct i.c. inoculation is not surprising (46). The reduction in mortality after i.c.…”

“…The HSV-1 gE deletion strain is impaired in neuronal spread, making it a novel vaccine candidate (25,26). A similar deletion was made in the gene encoding HSV-2 gE, and that mutant strain was also shown to be defective in neuronal spread (46). The current study evaluated whether the HSV-2 gE deletion strain, gE2-del virus, is safe and effective in animal models as a prophylactic and therapeutic vaccine.…”

“…at 5 PFU, which was the lowest dose evaluated. The defect in gE2-del virus is in neuroinvasion, that is, in its ability to reach the brain from peripheral sites (46). The mutant virus does not have a defect in its ability to replicate in neurons; therefore, death following direct i.c.…”

Function of glycoprotein E of herpes simplex virus requires coordinated assembly of three tegument proteins on its cytoplasmic tail

“…Moreover, it requires glycoproteins E and I (gE and gI, respectively) (1), which are not necessary for "cell-free" transmission (3). Consequently, HSV mutants lacking gE/gI are severely restricted for spread to neuronal cells (3)(4)(5)(6)(7)(8)(9)(10)(11). Remarkably, along with the core entry proteins, the gE/gI heterodimer is also required for HSV-induced cell fusion to produce syncytia (3,12,13).…”