Herpes Simplex Virus-1 targets the 2'-3'cGAMP importer SLC19A1 as an antiviral countermeasure.

To establish a successful infection, herpes simplex virus-1 (HSV-1), a virus with high seropositivity in the human population, must undermine host innate and intrinsic immune defense mechanisms, including the stimulator of interferon genes (STING) pathway. Recently it was discovered that not only Importance: HSV-1 has evolved multiple mechanisms to neutralize of the host's innate and intrinsic defense pathways, such as the STING pathway. Here, we identified an antiviral response in which extracellular 2'-3'cGAMP triggers IFN production via its transporter SLC19A1. Moreover, we report that HSV-1 blocks the functions of this transporter thereby impeding the antiviral response, suggesting exogenous 2'-3'cGAMP can act as an immunomodulatory molecule in uninfected cells to activate the STING pathway, and priming an antiviral state, similar to that seen in interferon responses. The details of this mechanism highlight important details about HSV-1 infections. This work presents novel findings about how HSV-1 manipulates the host's immune environment for viral replication and reveals details about a novel antiviral mechanism. These findings expand our understanding of how viral infections undermine host responses and may help in the development of better broad based antiviral drugs in the future.