Herpes Simplex Virus Type 1 Glycoprotein E Is Required for Axonal Localization of Capsid, Tegument, and Membrane Glycoproteins

Abstract

Herpes simplex virus type 1 (HSV-1) glycoprotein E (gE) promotes cell-to-cell spread at basolateral surfaces of epithelial cells, but its activity in neurons is less clear. We used the mouse retina infection model and neuronal cell cultures to define the spread phenotype of gE mutant viruses. Wild-type (WT) and gE-null (NS-gEnull) viruses both infected retina ganglion cell neurons; however, NS-gEnull viral antigens failed to reach the optic nerve, which indicates a defect in axonal localization. We evaluated two Fc receptor-negative gE mutant viruses containing four amino acid inserts in the gE ectodomain. One mutant virus failed to spread from the retina into the optic nerve, while the other spread normally. Therefore, the gE ectodomain is involved in axonal localization, and the Fc receptor and neuronal spread are mediated by overlapping but distinct gE domains. In the retina infection model, virus can travel to the brain via the optic nerve from presynaptic to postsynaptic neurons (anterograde direction) or via nerves that innervate the iris and ciliary body from postsynaptic to presynaptic neurons (retrograde direction). WT virus infected the brain by anterograde and retrograde routes, whereas NS-gEnull virus failed to travel by either pathway. The site of the defect in retrograde spread remains to be determined; however, infection of rat superior cervical ganglia neurons in vitro indicates that gE is required to target virion components to the axon initial segment. The requirement for gE in axonal targeting and retrograde spread highlights intriguing similarities and differences between HSV-1 and pseudorabies virus gE.Herpes simplex virus type 1 (HSV-1) infects skin, oral, ocular, and genital epithelial cells and spreads to axon fibers that innervate these tissues. The viral DNA, surrounded by capsid and tegument proteins, is transported to the neuronal cell body (3), where the DNA becomes latent in the nucleus. Transport of virus or virion components from epithelial cells to the neuron nucleus involves spread from epithelial cells to the axon terminus (cell-to-cell spread) and transport from the axon terminus to the nucleus (retrograde direction) (53). When the viral DNA reactivates from latency, virion components are produced in the neuron cell body which localize to the axon (axonal localization) and then travel along axon fibers to the axon terminus (anterograde direction) (53). The site for virion assembly in the neuron during reactivation infection remains controversial for alphaherpesviruses and is proposed to occur in the cell body (17), in axon shafts (31, 51), or at the axon terminus (26, 39). Finally, mature virions or virion subunits spread from the axon terminus to epithelial cells (cell-to-cell spread) to produce recurrent infections.Glycoprotein E (gE) is required for efficient HSV-1 spread from cell-to-cell within epithelial cells in vitro and in vivo, since gE-null virus produces smaller plaques than wild-type (WT) virus (18, 43), and causes smaller skin lesions at the inoculation site in t...

Transport and egress of herpes simplex virus in neurons

“…This interaction may be important for anterograde axonal transport of viral glycoprotein-containing vesicles. A series of studies using deletion mutants of HSV-1 and PrV that do not express pUS9 or gE have also supported a role for these VPs in anterograde axonal transport [96,101,[123][124][125]. To date, a direct link between either pUS9 or gE and kinesin has not been established.…”

Herpes Simplex Virus Type 1 Glycoprotein E Mediates Retrograde Spread from Epithelial Cells to Neurites

“…Viruses lacking either gE or gI form characteristically small plaques in cell culture and small inoculation site lesions in mice (4,9,18,40,58). In animal models, gE and gI also mediate viral spread in both anterograde and retrograde directions (4,19,44,56).…”

“…Viruses lacking either gE or gI form characteristically small plaques in cell culture and small inoculation site lesions in mice (4,9,18,40,58). In animal models, gE and gI also mediate viral spread in both anterograde and retrograde directions (4,19,44,56).In order to better understand the role of gE in HSV-1 retrograde neuronal spread, we employed a compartmentalized neuron culture system that has been used to study directional neuronal spread of PRV and West Nile virus (12,14,45). In the Campenot chamber system, neurites are contained in a compartment that is separate from their corresponding cell bodies.…”

Virion-Incorporated Glycoprotein B Mediates Transneuronal Spread of Pseudorabies Virus

“…This property has made alphaherpesviruses invaluable as neural circuit tracers in studies that aim to map the synaptic architecture of the CNS (14). However, the mechanisms that confer such specificity on the spread of infection are not well understood.The study of mechanisms underlying PRV trafficking revealed that the virally encoded membrane proteins Us9, glycoprotein E (gE), and gI are required for the efficient sorting of virions from an infected neuronal cell body into its cognate axon (6,26,29,44,49). Therefore, in the absence of any of these proteins, infection cannot be transmitted efficiently from a presynaptic to a postsynaptic cell (3,23).…”