Mechanism of herpes simplex virus type 1 latency in transgenic mouse models

Herpes Simplex Virus is a common cause of human blindness due to recurrent infections targeting the cornea. The virus remains latent in the neurons of trigeminal ganglia after traveling by axonal transport from the original acute infection in corneal epithelium and stroma. A better understanding of how latency and reactivation are regulated for this virus is the key to developing strategies of protection and prevention. The general hypothesis is that latency and reactivation of HSV infection are regulated by cellular transcription factors that modulate genes needed for productive viral infection. HSV immediate early (EE) gene transcription may be repressed by cellular transcriptional factors or it may fail to be activated because of a lack of appropriate activating transcriptional factors thus resulting in a latent infection in sensory neurons. Viral IE gene transcription is hypothesized to be reinitiated following a change in cellular transcription factors such as may occur following neuronal damage or systemic stress. This activation of viral gene expression from the latent genome leads to reactivation of HSV-1. This project examines whether host proteins can regulate HSV-1 IE gene promoters (ICP0, ICP27), an early (E) gene promoter (TK), and a late (L) gene promoter (gC) in transgenic mouse models without viral proteins. The transgenic mouse models were examined for up-regulation of each HSV-1 IE, E, and L promoter transgene using stimuli that represent natural means of reactivating virus. The significance of the regulatory sequence, TAATGARAT, of HSV-1 IE genes was also examined. The results showed that: (1) Neurons differentially activate HSV-1 IE gene promoters (ICP27, ICPO, ICP4) in the absence of viral proteins; (2) The level of activation of these promoters in trigeminal ganglia neurons was increased by neuronal damage; (3) The level of activation also depends on age of the mice; (4) The TK promoter is activated by neurons in the brain but not in trigeminal ganglia; (5) The gC promoter is not activated by neurons; and (6) Mutation of 50% of the TAAT within the two TAATGARAT sequences of the ICP4 promoter does not abolish expression in neurons.