Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

Lee, Sung-Seok; Ives, Angela M.; Bertke, Andrea S.

doi:10.1128/jvi.00468-15

Cited by 36 publications

(32 citation statements)

References 32 publications

(43 reference statements)

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“…Of these, HSV represents a particularly attractive target for several reasons. Unlike infections such as HIV, in which persistent genomes are maintained in cells scattered throughout the body, latent HSV genomes are restricted to neurons — specifically neuronal cell bodies of sensory and autonomic ganglia (34). Thus, delivery of endonucleases to the relevant cells, which is a critical determinant of ultimate success (11), is greatly simplified.…”

Section: Discussionmentioning

confidence: 99%

In vivo disruption of latent HSV by designer endonuclease therapy

Aubert¹,

Madden²,

Loprieno³

et al. 2016

JCI Insight

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A large portion of the global population carries latent herpes simplex virus (HSV), which can periodically reactivate, resulting in asymptomatic shedding or formation of ulcerative lesions. Current anti-HSV drugs do not eliminate latent virus from sensory neurons where HSV resides, and therefore do not eliminate the risk of transmission or recurrent disease. Here, we report the ability of HSV-specific endonucleases to induce mutations of essential HSV genes both in cultured neurons and in latently infected mice. In neurons, viral genomes are susceptible to endonuclease-mediated mutagenesis, regardless of the time of treatment after HSV infection, suggesting that both HSV lytic and latent forms can be targeted. Mutagenesis frequency after endonuclease exposure can be increased nearly 2-fold by treatment with a histone deacetylase (HDAC) inhibitor. Using a mouse model of latent HSV infection, we demonstrate that a targeted endonuclease can be delivered to viral latency sites via an adeno-associated virus (AAV) vector, where it is able to induce mutation of latent HSV genomes. These data provide the first proof-of-principle to our knowledge for the use of a targeted endonuclease as an antiviral agent to treat an established latent viral infection in vivo.

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Section: Discussionmentioning

confidence: 99%

In vivo disruption of latent HSV by designer endonuclease therapy

Aubert¹,

Madden²,

Loprieno³

et al. 2016

JCI Insight

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“…Sensory trigeminal ganglia (TG), sympathetic superior cervical ganglia (SCG), and parasympathetic ciliary ganglia (CG) were removed from 6-week-old female Swiss Webster mice, dissociated, and plated on Matrigel-coated Lab-Tek II chamber slides (Thermo Scientific) as described previously (32,56). Briefly, ganglia were digested in papain, collagenase, and dispase (Worthington), followed by mechanical trituration.…”

Section: Methodsmentioning

confidence: 99%

Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons

Ives

Bertke

2017

J Virol

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Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with the exacerbation of clinical symptoms and the induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive HSV-1 and HSV-2 infections within sensory and autonomic neurons, we analyzed viral DNA and the production of viral progeny after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal ganglion (TG) and sympathetic superior cervical ganglion (SCG) neurons expressed adrenergic receptors (activated by epinephrine) and the glucocorticoid receptor (activated by corticosterone). Productive HSV infection colocalized with these receptors in SCG but not in TG neurons. In productively infected neuronal cultures, epinephrine treatment significantly increased the levels of HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased the levels of HSV-2 DNA replication and production of viral progeny in SCG neurons but not in TG neurons. Thus, the stress-related hormones epinephrine and corticosterone selectively modulate acute HSV-1 and HSV-2 infections in autonomic, but not sensory, neurons.IMPORTANCE Stress exacerbates acute disease symptoms resulting from HSV-1 and HSV-2 infections and is associated with the appearance of recurrent skin lesions in millions of people. Although stress hormones are thought to impact HSV-1 and HSV-2 through immune system suppression, sensory and autonomic neurons that become infected by HSV-1 and HSV-2 express stress hormone receptors and are responsive to hormone fluctuations. Our results show that autonomic neurons are more responsive to epinephrine and corticosterone than are sensory neurons, demonstrating that the autonomic nervous system plays a substantial role in HSV pathogenesis. Furthermore, these results suggest that stress responses have the potential to differentially impact HSV-1 and HSV-2 so as to produce divergent outcomes of infection.KEYWORDS herpes simplex virus, HSV-1, HSV-2, epinephrine, corticosterone, stress, reactivation

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“…erpes simplex virus 1 (HSV-1) is a highly prevalent human pathogen that establishes lifelong infection in the neurons of sensory and autonomic ganglia (1,2). Initial infection and lytic replication at mucosal sites are followed by infection of innervating axonal termini of sensory neurons.…”

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confidence: 99%

Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons

Katzenell

Leib

2016

J Virol

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IMPORTANCEHerpes simplex virus type 1 (HSV-1) is a ubiquitous virus and a significant cause of morbidity and some mortality. It is the causative agent of benign cold sores, but it can also cause blindness and life-threatening encephalitis. The success of HSV-1 is largely due to its ability to establish lifelong latent infections in neurons and to occasionally reactivate. The exact mechanisms by which neurons defend against virus infection is poorly understood, but such defense is at least partially mediated by autophagy, an intracellular pathway by which pathogens and other unwanted cargoes are degraded. The study demonstrates and investigates a new autophagic structure that appears to be specific to the interaction between neurotropic herpesviruses and murine primary sensory neurons. This work may therefore have important implications for our understanding of latency and reactivation. Herpes simplex virus 1 (HSV-1) is a highly prevalent human pathogen that establishes lifelong infection in the neurons of sensory and autonomic ganglia (1, 2). Initial infection and lytic replication at mucosal sites are followed by infection of innervating axonal termini of sensory neurons. Virions then travel in a retrograde direction to the soma, where they may replicate or immediately establish latency, depending partly on the infected neuronal subtype (3). Virions resulting from periodic reactivation events travel in an anterograde direction along the axon, allowing reinfection of the oral epithelium, thereby facilitating viral shedding and host-to-host transmission (2).Innate immune responses are critical in controlling virulence of HSV-1 and many other viruses through a variety of antiviral pathways (4-12), and viruses have coevolved to counter these host responses (13)(14)(15)(16)(17)(18)(19)(20). Cells detect the presence of incoming virus through pattern recognition receptors (21, 22) that, in turn, lead to the activation of pivotal transcription factors such as IRF (5, 23) and NF-B (24). These factors subsequently induce the production of type I interferon (IFN), which drives IFN-stimulated gene (ISG) expression (25) through a JAK-STAT-dependent pathway (26,27). This further stimulates production of type I IFN and ISGs to establish an antiviral state that consists of transcriptional and translational arrest, cytokine production, and apoptosis (28,29).Defects in innate immunity are often associated with increased susceptibility to HSV infection in both mice and humans, with frequent neurological sequelae (8,12,(30)(31)(32). That said, the IFNdriven responses of neurons themselves are muted and atypical (12,33). Nondestructive clearance is especially critical for postmitotic adult neurons, a population of irreplaceable cells that is essential for both the success and survival of the host. Indeed, there is mounting evidence that neurons depend on autophagy rather than inflammatory or cell-destructive responses for the control of intracellular pathogens (34-37). Autophagy is a highly conserved response to starvation, during...

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Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

Cited by 36 publications

References 32 publications

In vivo disruption of latent HSV by designer endonuclease therapy

In vivo disruption of latent HSV by designer endonuclease therapy

Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons

Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons

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