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. IMPORTANCEHerpes 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.

Establishment of HSV1 Latency in Immunodeficient Mice Facilitates Efficient In Vivo Reactivation

“…BS were not assayed but in assaying necropsy Tg and BS from mice that succumbed to spontaneous reactivation we observed instances where infectious virus was present only in the BS (Fig. 2A), which is consistent with reactivation also occurring in the BS as reported recently for mice subjected to HS [30]. Overall, the data show HSV1 was efficiently reactivated in vivo in both LD and HD latently infected Rag mice, but remarkably was amplified resulting in uncontrolled replication and fatal HSE only in HD but not LD Rag mice.…”

Resident T Cells Are Unable To Control Herpes Simplex Virus-1 Activity in the Brain Ependymal Region during Latency

“…2A). LAT expression was also examined in the BS as it receives sensory neural projections from the TG and has been reported as a site of HSV-1 reactivation (40). At 30 DPI, the level of LAT expression within the BS was similar to those found in the EP but also far less than transcripts expressed in the TG (Fig.…”

Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 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, however, Yao et al (2014) showed that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. In fact, the brain yields reactivated virus earlier and more efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus.…”