Cultured vestibular ganglion neurons demonstrate latent HSV1 reactivation

Abstract

Objectives/Hypothesis Vestibular neuritis is a common cause of both acute and chronic vestibular dysfunction. Multiple pathologies have been hypothesized to be the causative agent of vestibular neuritis; however, whether herpes simplex type I (HSV1) reactivation occurs within the vestibular ganglion has not been demonstrated previously by experimental evidence. We developed an in vitro system to study HSV1 infection of vestibular ganglion neurons (VGNs) using a cell culture model system. Study design basic science study. Results Lytic infection of cultured rat VGNs was observed following low viral multiplicity of infection (MOI). Inclusion of acyclovir suppressed lytic replication and allowed latency to be established. Upon removal of acyclovir, latent infection was confirmed with reverse-transcription polymerase chain reaction and by RNA fluorescent in situ hybridization for the latency-associated transcript (LAT). 29% cells in latently infected cultures were LAT positive. The lytic IPC27 transcript was not detected by reverse-transcription polymerase chain reaction (RT-PCR). Reactivation of HSV1 occurred at a high frequency in latently infected cultures following treatment with trichostatin A (TSA), a histone deactylase inhibitor. Conclusions VGNs can be both lytically and latently infected with HSV1. Furthermore, latently infected VGNs can be induced to reactivate using TSA. This demonstrates that reactivation of latent HSV1 infection in the vestibular ganglion can occur in a cell culture model, and suggests that reactivation of HSV1 infection a plausible etiologic mechanism of vestibular neuritis.

A Perspective on Recurrent Vertigo

“…The chemicals elevated in the stress response (cortisol and adrenalin) are capable of allowing the virus to reactivate [40] and cause symptoms by destroying groups (clusters) of ganglion cells. Reactivation of latent HSV-1 has been confirmed in animal-cultured (rat) vestibular ganglion cells [34]. A major deterrent to the acceptance of a viral neuropathy in these common vestibular syndromes is the lack of history pointing to a recognizable viral insult to the ear.…”

“…This group of viruses has a propensity for invading sensory neurons, establishing latency within the nucleus of the ganglion cell, and becoming reactivated at a later (years) date during a period of extreme stress [32,33]. The best known members of this group of viruses are herpes simplex HSV types 1 and 2, and Herpes zoster (varicella) virus [34]. Other members of this family of NT viruses are cytomegalo-inclusion virus, pseudorabies and Epstein-Barr virus.…”

A Cell Culture Model of Latent and Lytic Herpes Simplex Virus Type 1 Infection in Spiral Ganglion

“…There are two previously published models of in vitro HSV-1 lytic and latent infection in primary cultures of neuronal cells from the temporal bone. These are in vestibular ganglion neurons [34] and in geniculate ganglion neurons [35]. In this study, we have shown that infection of SGN culture with HSV-1 in the presence of ACV, which suppresses lytic replication, resulted in latent infection.…”

Shared ancestry of herpes simplex virus 1 strain Patton with recent clinical isolates from Asia and with strain KOS63

“…Patton has been used extensively in laboratory studies, including, but not limited to, early studies of mRNA splicing (Watson et al, 1981), identification of lytic cycle proteins involved in viral DNA replication (Graham et al, 1978), drug resistance (Furman et al, 1981), pathogenesis (Bonneau and Jennings, 1989; Mohr et al, 2001; Morahan et al, 1981; Ward et al, 2003), and oncolytic virus development (Pourchet et al, 2016; Taneja et al, 2001). The GFP-US11 recombinant has served as a versatile reporter simplifying the development of in vitro latency models (Camarena et al, 2010; Kuhn et al, 2012; Pourchet et al, 2017; Roehm et al, 2011), and has been used in more detailed studies of reactivation (Kim et al, 2012), maintenance of latency by nerve growth factor signaling (Camarena et al, 2010; Kobayashi et al, 2012), and the suppression of reactivation by interferon (Linderman et al, 2017). Understanding the genomic structure of Patton and its evolutionary relationship to other strains and clinical isolates is therefore important.…”