Reactivation of HSV-1 following explant of tree shrew brain

J Neurovirol. 2016 Jun;22(3):293-306. doi: 10.1007/s13365-015-0393-4. Epub 2015 Oct 26.


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.

Keywords: CNS; Explant cocultivation; HSV-1; Latency; Reactivation; Tree shrew.

MeSH terms

  • Animals
  • Brain Stem / metabolism
  • Brain Stem / pathology
  • Brain Stem / virology
  • Disease Models, Animal
  • Encephalitis, Herpes Simplex / genetics
  • Encephalitis, Herpes Simplex / metabolism
  • Encephalitis, Herpes Simplex / pathology
  • Encephalitis, Herpes Simplex / virology*
  • Female
  • Gene Expression Regulation, Viral*
  • Herpesvirus 1, Human / genetics*
  • Herpesvirus 1, Human / metabolism
  • Herpesvirus 1, Human / pathogenicity
  • Host Specificity
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Olfactory Bulb / metabolism
  • Olfactory Bulb / pathology
  • Olfactory Bulb / virology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tissue Culture Techniques
  • Trigeminal Ganglion / metabolism
  • Trigeminal Ganglion / pathology
  • Trigeminal Ganglion / virology*
  • Tupaiidae
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Virus Activation*
  • Virus Latency*


  • Immediate-Early Proteins
  • MicroRNAs
  • RNA, Messenger
  • herpes simplex virus, type 1 protein ICP4
  • latency associated transcript, herpes simplex virus-1
  • Ubiquitin-Protein Ligases
  • Vmw110 protein, Human herpesvirus 1