Varicella-Zoster Virus Glycoprotein I Is Essential for Spread in Dorsal Root Ganglia and Facilitates Axonal Localization of Structural Virion Components in Neuronal Cultures

Abstract

bNeurons of the sensory ganglia are the major site of varicella-zoster virus (VZV) latency and may undergo productive infection during reactivation. Although the VZV glycoprotein E/glycoprotein I (gE/gI) complex is known to be critical for neurovirulence, few studies have assessed the roles of these proteins during infection of dorsal root ganglia (DRG) due to the high human specificity of the virus. Here, we show that the VZV glycoprotein I gene is an important neurotropic gene responsible for mediating the spread of virus in neuronal cultures and explanted DRG. Inoculation of differentiated SH-SY5Y neuronal cell cultures with a VZV gI gene deletion strain (VZV rOka⌬gI) showed a large reduction in the percentage of cells infected and significantly smaller plaque sizes in a comparison with cultures infected with the parental strain (VZV rOka). In contrast, VZV rOka⌬gI was not significantly attenuated in fibroblast cultures, demonstrating a cell type-specific role for VZV gI. Analysis of rOka⌬gI protein localization by immunofluorescent staining revealed aberrant localization of viral glycoprotein and capsid proteins, with little or no staining present in the axons of differentiated SH-SY5Y cells infected with rOka⌬gI, yet axonal vesicle trafficking was not impaired. Further studies utilizing explanted human DRG indicated that VZV gI is required for the spread of virus within DRG. These data demonstrate a role for VZV gI in the cell-to-cell spread of virus during productive replication in neuronal cells and a role in facilitating the access of virion components to axons. V aricella-zoster virus (VZV) is the etiological agent of the human disease varicella (chickenpox) (1). Following primary infection, the virus establishes latency within neurons of the sensory ganglia (2, 3), from where it may reactivate to result in the secondary clinical disease herpes zoster (shingles) (4). Herpes zoster may be followed by a state of debilitating, long-term pain known as postherpetic neuralgia (PHN), which is commonly resistant to many traditional pain therapies (3,5,6).VZV glycoprotein I (gI) is a type I membrane protein encoded by open reading frame 67 (ORF67) and functions primarily as a heterodimer with the most abundant VZV protein, gE (7). Although gI is dispensable in cell culture, deletion of the gene results in an impairment of syncytium formation, delayed replication, and a decrease in infectious virus yields within melanoma cells (8).In the context of neuronal infection, gI has been shown to be dispensable in a rat model of persistent VZV infection, although this host is nonpermissive (9). In a severe combined-immunodeficiency human (SCIDhu) mouse model of VZV infection utilizing human-xenografted dorsal root ganglia (DRG), infection with a VZV mutant lacking the gI gene (rOka⌬gI) resulted in prolonged replication within the DRG and an inability to transition to a persistent state, normally characterized by limited viral transcription (10). In addition, mutation of the cysteine-rich region in VZV gE responsible for ...

Low Trend for VZV-Associated Disease Patients to Visit Neurologists

“… 43 ZAP, especially PHN, is a specific type of neuropathy in which the virulence VZV is transmitted from the neuron to the axon endings, 44 causing axon destruction from the inside out. 45 As VZV-induced peripheral axonal damage causes ZAP, it raises the question as to why there is no targeted nerve treatment available. The treatment goal for patients with ZAP should not only focus on pain relief; but also on protecting and repairing damaged nerves.…”

Electrophysiological characteristics of the frontal nerve in patients with herpetic ophthalmic neuralgia

“…V1 is purely a sensory nerve, and VZV‐related neuropathy causes demyelination and axonal damage to varying degrees …”

“…V1 is purely a sensory nerve, and VZV-related neuropathy causes demyelination and axonal damage to varying degrees. [35][36][37][38] Among the ROCs of the conduction velocities, the SCVs of 3 nerves predicted HON. The sensitivities of the SCVs in our study were similar to the results of a study by Oh et al, 32 in which the overall diagnostic sensitivities of the SCVs were 69% with an on-nerve needle.…”