title: In vivo reactivation of latent herpes simplex virus 1 in mice can occur in the brain before occurring in the trigeminal ganglion.
abstract: Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ.
  
  
  OBJECTIVE
  Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yao
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Pin
authors.initials: P
authors.lastname: Ling
authors.affiliation: Statistical Analysis Laboratory, Institute of Education, College of Social Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Yuk-Ying
authors.initials: YY
authors.lastname: Tung
authors.affiliation: Department of Ophthalmology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Sheng-Min
authors.initials: SM
authors.lastname: Hsu
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan, Republic of China Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China shunhua@mail.ncku.edu.tw shengmin@mail.ncku.edu.tw.
authors.forename: Shun-Hua
authors.identifier: http://orcid.org/0000-0002-4585-9279
authors.initials: SH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000821:virology*; D002522:Chlorocebus aethiops; D005334:Fever / Q000821:virology; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000821:virology*; D014709:Vero Cells; D019562:Viral Load; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology