The Neuroimmunology of Viral Infection

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DESCRIPTION (provided by applicant): Based on the seroprevalence rates, between 150 and 200 million Americans are latently infected with herpes simples virus type 1 (HSV-1) of which 20% will experience recurrent reactivation of latent virus. Most of the morbidity associated with HSV-1 infection is a result of repeated reactivation of latent virus that occurs throughout the lifetime of the host. Sensory neurons (dorsal root or trigeminal ganglion [TG]) serve as a reservoir for latent HSV-1 and upon stress (e.g., fever, trauma) will reactivate. Upon reactivation, the virus is transported (via anterograde) to sites proximal to the original portal of entry where the virus will replicate inducing a strong inflammatory response. The mechanism(s) associated with reactivation are not understood. Moreover, the immune response to acute and latent virus infection is complex and multiple components of both the adaptive and innate immune systems are thought to counter the virus. However, HSV-1 is highly prevalent and its success is thought to reside with the immune evading mechanisms that it has developed through co-evolution with the human host. Recently, this lab has focused on type I interferons (IFN), a family of potent anti-viral cytokines secreted in response to viral infection including HSV-1. A transgenic mouse model expressing IFN-alpha I in the nervous system and plasmid constructs expressing a number of type I IFN transgenes have all been generated to begin to elucidate those mechanisms utilized by the host to control viral replication focusing on infections of the nervous system. The goal of this application is to address the hypothesis that type I IFNs antagonize HSV-1 replication, spread, and reactivation through the induction of two IFN stimulatory genes including OAS and PKR. To achieve this goal, we plan to: 1) characterize the anti-viral efficacy and the induction of the IFN-stimulatory gene cascade as a result of transfection/transduction with type I IFN plasmid or viral constructs in response to HSV-1 infection using in vitro and in vivo models and 2) characterize the reactivation potential of latent HSV-1 following transfection/transduction with type I IFN transgenes using in vitro and in vivo models. It is anticipated that in accomplishing these aims, significant insight into the mechanism(s) associated with controlling viral replication and reactivation in the nervous system can be achieved.