RESUMEN
IMPORTANCE: Herpes simplex virus-1 (HSV-1) is a human pathogen known to cause cold sores and genital herpes. HSV-1 establishes lifelong infections in our sensory neurons, with no cure or vaccine available. HSV-1 can reactivate sporadically and travel back along sensory nerves, where it can form lesions in the oral and genital mucosa, eye, and skin, or be shed asymptomatically. New treatment options are needed as resistance is emerging to current antiviral therapies. Here, we show that interferons (IFNs) are capable of blocking virus release from nerve endings, potentially stopping HSV-1 transmission into the skin. Furthermore, we show that IFNγ has the potential to have widespread antiviral effects in the neuron and may have additional effects on HSV-1 reactivation. Together, this study identifies new targets for the development of immunotherapies to stop the spread of HSV-1 from the nerves into the skin.