Antiviral responses play a critical role in the management of neuronal HSV-1 infections. Deficiencies in antiviral activity have long been associated with enhanced frequency and severity of disease. Two antiviral proteins--Interferon Regulatory Factor 3 (IRF3) and Nuclear Factor Kappa B (NF-κB)--are observed to have document- ed effects on HSV-1 viral replication, neuronal disease, and host mortality. Their importance, while broadly identified, has not been clearly defined in regard to their specific antiviral roles during HSV-1 infections. Our preliminary data suggests that both IRF3 and NF-κB play different, yet significant, roles in the management of neuronal HSV-1 infections. We observed that inhibition of IRF3 led to enhanced neuronal replication and spread in a published model of neuronal HSV-1 infection. In a model of silent HSV-1 infection, we saw that inhibiting NF-κB prevented establishment of silent infections and also promoted their reactivation. These results have led us to hypothesize that IRF3 and NF-κB impact neuronal HSV-1 infection by affecting neuronal trans- mission and genome silencing, respectively. To test our hypothesis, we will experimentally alter the activity of these molecules to observe their effects on neuronal infection. The effect of IRF3 on neuronal transmission will be assessed in Aim 1 by measuring neuronal replication, spread, and the rate of virion transport down axons. In Aim 2, we will further explore the effects of NF-κB activity on silencing, as well as compare how reactivation mediated by NF-κB inhibition compares to other known reactivators of silent HSV-1 infection. These experiments will contribute to a currently lacking understanding of how neuronal HSV-1 infections are controlled. Our results will serve as a foundation for further exploration regarding how IRF3 and NF-κB mediate their effects on transmission and latency, respectively. The increased understanding of these factors will pave the way for more effective management of HSV-1 disease through enhanced antiviral responses.