Neuronal Subtype Determines Herpes Simplex Virus 1 Latency-Associated-Transcript Promoter Activity during Latency

Abstract

Herpes simplex virus (HSV) latency in neurons remains poorly understood, and the heterogeneity of the sensory nervous system complicates mechanistic studies. In this study, we used primary culture of adult trigeminal ganglion (TG) mouse neurons in microfluidic devices, and an model, to examine the subtypes of sensory neurons involved in HSV latency. HSV-infected neurofilament heavy-positive neurons (NefH) were more likely to express Latency-Associated Transcripts (LATs) relative to infected neurofilament heavy-negative neurons (NefH). This differential expression of the LAT promoter correlated with differences in HSV-1 early infection that manifested as differences in the efficiency with which HSV particles reached the cell body following infection at the distal axon. , we further identified a specific subset of NefH neurons which co-expressed Calcitonin Gene Related Peptide α (NefH CGRP) as the sensory neuron subpopulation with the highest LAT promoter activity following HSV-1 infection. Finally, an early-phase reactivation assay showed HSV-1 reactivating in NefH CGRP neurons, although other sensory neuron subpopulations were also involved. Together, these results show that sensory neurons expressing neurofilaments exhibit enhanced LAT promoter activity. We hypothesize that reduced efficiency of HSV-1 invasion at an early phase of infection may promote efficient establishment of latency in NefH neurons due to initiation of the antiviral state preceding arrival of the virus at the neuronal cell body. While the outcome of HSV-1 infection of neurons is determined by a broad variety of factors neuronal subtypes are likely to play differential roles in modulating the establishment of latent infection. Two pivotal properties of HSV-1 make it a successful pathogen. Firstly, it infects neurons which are immune-privileged. Secondly, it establishes latency in these neurons. Together, these properties allow HSV to persist for the lifetime of its host. Neurons are diverse and highly organized cells, with specific anatomical, physiological and molecular characteristics. Previous work has shown that establishment of latency by HSV-1 does not occur equally in all types of neurons. Our results show that the kinetics of HSV infection and levels of latency-related gene expression differ in certain types of neurons. The neuronal subtype infected by HSV is therefore a critical determinant of the outcome of infection and latency.

The ESCRT-Related ATPase Vps4 Is Modulated by Interferon during Herpes Simplex Virus 1 Infection

“…That said, not all Vps4-weak neurons were LC3 cluster positive. This suggests that TG neurons do not respond equally to IFN, which is expected since these neurons are heterogeneous (46). Finally, we wished to address whether the IFN-induced decrease of Vps4 is a neuron-specific response or represents a more broad-spectrum antiviral response.…”

Abortive herpes simplex virus infection of nonneuronal cells results in quiescent viral genomes that can reactivate

“…In the case of herpes simplex virus 1 (HSV-1), spontaneous latency is established within sensory or sympathetic peripheral neurons. Even in these neuronal populations, specific subtypes vary in the establishment of latency and in their signals of reactivation (6,7), suggesting that there is more than one mechanism to establish and maintain latency.…”

Strength in diversity: Understanding the pathways to herpes simplex virus reactivation

“…There is great diversity in sensory and sympathetic neurons, which can differ in their physiological, anatomical, structural and molecular properties (DeLeón et al, 1994; Gold et al, 1997; Lallemend and Ernfors, 2012; Liu and Ma, 2011), and this may have significant implications for HSV infection. Certain sensory neuron subtypes, characterized by the presence of neurofilaments (NefH) and calcitonin gene related peptide α (CGRP), as well as positive staining with the A5 antibody, have the highest levels of LAT promoter activity, are less permissive for HSV-1 productive infection, and preferentially undergo early-phase reactivation (Bertke et al, 2009; 2011; Cabrera et al, 2018). Sympathetic and sensory neurons also vary in regards to their expression of different stress hormone receptors, neurotrophin receptors, and ion channels, which also influence how these neurons respond to cues during both acute infection and reactivation from latency (DeLeón et al, 1994; Gold et al, 1997; Lallemend and Ernfors, 2012; Liu and Q. Ma, 2011).…”