Abstract

Herpes Simplex Virus type I (HSV-1) latently infects peripheral nervous system (PNS) sensory neurons, and its reactivation leads to recurring cold sores. The reactivated HSV-1 can travel retrograde from the PNS into the central nervous system (CNS) and is known to be causative of Herpes Simplex viral encephalitis. HSV-1 infection in the PNS is well documented, but little is known on the fate of HSV-1 once it enters the CNS. In the murine model, HSV-1 genome persists in the CNS once infected through an ocular route. To gain more details of HSV-1 infection in the CNS, we characterized HSV-1 infection of the tree shrew (Tupaia belangeri chinensis) brain following ocular inoculation. Here, we report that HSV-1 enters the tree shrew brain following ocular inoculation and HSV-1 transcripts, ICP0, ICP4, and LAT can be detected at 5 days post-infection (p.i.), peaking at 10 days p.i. After 2 weeks, ICP4 and ICP0 transcripts are reduced to a basal level, but the LAT intron region continues to be expressed. Live virus could be recovered from the olfactory bulb and brain stem tissue. Viral proteins could be detected using anti-HSV-1 antibodies and anti-ICP4 antibody, during the acute stage but not beyond. In situ hybridization could detect LAT during acute infection in most brain regions and in olfactory bulb and brain stem tissue well beyond the acute stage. Using a homogenate from these tissues’ post-acute infection, we did not recover live HSV-1 virus, supporting a latent infection, but using a modified explant cocultivation technique, we were able to recover reactivated virus from these tissues, suggesting that the HSV-1 virus latently infects the tree shrew CNS. Compared to mouse, the CNS acute infection of the tree shrew is delayed and the olfactory bulb contains most latent virus. During the acute stage, a portion of the infected tree shrews exhibit symptoms similar to human viral encephalitis. These findings, together with the fact that tree shrews are closely related to primates, provided a valuable alternative model to study HSV-1 infection and pathogenesis in the CNS.

Highlights

  • Following eye infection, Herpes simplex virus type 1(HSV-1) is transferred by fast axonal transport to the nuclei of trigeminal ganglia sensory neurons, in which it forms a latent infection

  • The reactivated virus can spread to the central nervous system (CNS), where it may lead to Herpes Simplex Virus encephalitis (HSE), the most common cause of sporadic and often fatal encephalitis (Kastrukoff et al 1981; Lundberg et al 2008)

  • Tree shrews were anesthetized with ketamine, followed by ocular scarification, 1×106 PFU of HSV-1 17+ virus in PBS solution was applied to each eye

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Summary

Introduction

Herpes simplex virus type 1(HSV-1) is transferred by fast axonal transport to the nuclei of trigeminal ganglia sensory neurons, in which it forms a latent infection. Reactivation of this latent infection leads to productive viral infection at the peripheral site of inoculation, which can cause skin lesions and herpes simplex keratitis (HSK). We were able to recover reactivated virus from brain stem and olfactory bulb Taken together, these results demonstrated that HSV-1 latently infects the CNS of tree shrew

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