Herpes simplex virus type 1 gene expression and reactivation of latent infection in the central nervous system

Abstract

Restricted gene expression takes place during latent infection of herpes simplex virus type 1 (HSV-1) in the human peripheral nervous system and has been linked with viral reactivation. The state of HSV-1 gene expression in the central nervous system (CNS) during latency is unclear and we, therefore, examined gene expression in the brainstem of experimental mice and normal humans. Only part of the transcription pattern present during latent infection in peripheral sensory ganglia (PSG) was identified in the human brainstem by in situ hybridization and Northern blot analysis for HSV-1-specific transcripts. Instead of three HSV-1 latency-associated transcripts (LATs) present in PSG and demonstrated by Northern blot analysis, only one was identified in mouse brainstem and none was detected in human brainstem. These findings might be attributed to the relatively low amounts of HSV-1-specific latency-associated RNAs in brainstem tissue. Combined with our inability to reactivate HSV-1 from explanted mouse brainstem, these findings suggest that tissue levels of latency-associated gene expression play a role in HSV-1 reactivation and have relevance to the very low incidence of HSV-1-induced CNS disease compared with peripheral mucocutaneous disease.

Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice

“…This is due to both complementation and generation of neuroinvasive recombinants (70) and occurs with mixtures of HSV-1 KOS plus F (parental strain of G207) (73). There have been only a few reports of attempts to establish HSV-1 latency models in the CNS, most unable to demonstrate reactivation (35,45,72,75,85). For example, using a variety of explant protocols with mouse brainstem, Steiner et al were unable to demonstrate any evidence of reactivation in 44 samples where reactivation from trigeminal ganglia was readily apparent (72).…”

“…There have been only a few reports of attempts to establish HSV-1 latency models in the CNS, most unable to demonstrate reactivation (35,45,72,75,85). For example, using a variety of explant protocols with mouse brainstem, Steiner et al were unable to demonstrate any evidence of reactivation in 44 samples where reactivation from trigeminal ganglia was readily apparent (72). In an HSV-1 latency model established in motor neurons of the spinal cord, explanting spinal cord did not lead to viral reactivation, in contrast to a Animals were observed from 60 to 240 days p.i.…”

Novel Less-Abundant Viral MicroRNAs Encoded by Herpes Simplex Virus 2 Latency-Associated Transcript and Their Roles in Regulating ICP34.5 and ICP0 mRNAs

“…Deletion of the LAT promoter in both HSV-1 and HSV-2 reduces the efficiency of reactivation (25,28,35,38,45,47,50). The hypothesized mechanisms by which LAT could act include inhibition of replication during acute infection of neurons via an antisense mechanism (13,37,39), thus promoting neuronal survival. The HSV-1 LAT is currently believed to act at least in part by increasing the establishment or maintenance of latency (35,45), likely via an effect on the survival of acutely infected neurons (44).…”

Latent Infection with Herpes Simplex Virus Is Associated with Ongoing CD8+T-Cell Stimulation by Parenchymal Cells within Sensory Ganglia

“…It was thought that this silence led to a state that was largely invisible to the immune system. Evidence supporting LAT expression in the absence of lytic gene and protein expression was originally provided by both human (5,14,21) and animal studies (15,51,52) of latently infected ganglia. However, with the evolution of more sensitive detection methods, the transcription of several lytic genes has now been demonstrated in latently infected ganglia (22,32), with evidence from murine studies suggesting some level of lytic protein expression in a small proportion of latently infected neurons (18).…”