Abstract
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus able to reach the central nervous system (CNS) after primary infection in oronasal mucosa. HSV-1 establishes latency inside neurons due the repression of its gene expression process, which is related to periodic reactivations in response to cellular stress conditions, constituting a risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). The immediate-early gene Arc plays an essential role in neuronal morphology, synaptic plasticity and memory formation. Arc acts as a hub protein, interacting with components of the endocytic machinery required for AMPA receptor (AMPAR) recycling as well as with proteins of the post-synaptic density and actin cytoskeleton. However, to date, no studies have evaluated whether persistent neurotropic HSV-1 infection modulates the expression or function of Arc protein in brain tissue. Here, we report that neuronal in vivo and in vitro infection of HSV-1 significantly increases Arc protein levels, showing a robust perinuclear distribution in neuronal cell lines, a process that is dependent on an active HSV-1 replication cycle. Finally, we found that silencing Arc protein caused a decrease in HSV-1 proteins and viral progeny, suggesting that Arc is involved in the lifecycle of HSV-1. Our studies strongly suggest that pathogenicity of HSV-1 neuronal reactivations in humans could be mediated in part by Arc neuronal upregulation and its potential role in endocytic trafficking and AMPA-neuronal function impairment. Further studies are necessary to define whether this phenomenon could have repercussions in cognition and learning processes in infected individuals.
Highlights
Herpes simplex virus type 1 (HSV-1) is a ubiquitous and neurotropic virus associated with cold sores that affects close to 68% of the adult population worldwide
We sought to elucidate whether neurotropic HSV-1 infection could have a role in Arc protein expression, a protein highly implicated in synaptic plasticity
Based on our results showing that HSV-1 infection causes a significant increase in Arc protein levels, we investigated whether Arc could be participating in AMPA receptor (AMPAR) endocytosis during HSV-1 infection in neuronal cells
Summary
Herpes simplex virus type 1 (HSV-1) is a ubiquitous and neurotropic virus associated with cold sores that affects close to 68% of the adult population worldwide. HSV-1 establishes and maintains a lifelong latent infection in peripheral neurons with frequent reactivation episodes (Davidovici et al, 2006; Xu et al, 2006). Once the viral genome enters the neuronal nucleus, one of two processes begins either productive replication or repression of lithic genes, leading to the establishment of latency (Ortiz et al, 2003). An exciting issue is whether recurrent viral reactivations at the neuronal level could cause neuronal damage or neurodysfunction repeatedly (Ando et al, 2008; Conrady et al, 2010; Martin et al, 2014a; Harris and Harris, 2015; Otth et al, 2016) It is still unknown whether neuronal HSV-1 infection could have an impact on synaptic plasticity
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