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

Abstract

The extracellular addition of the STING agonist, 2-3cGAMP, induces an antiviral state that inhibits HSV-1 replication in a cell type dependent manner via the transportation of the cyclic-dinucleotide through the folate antiporter SLC19A1. To establish a successful infection, herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population, must undermine a multitude of host innate and intrinsic immune defense mechanisms, including key players of the STimulator of INterferon Genes (STING) pathway. Herein, we report that HSV-1 infection results in the reduction of SLC19A1 transcription, translation, and importantly, the rapid removal of SLC19A1 from the cell surface of infected cells. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2'-3'cGAMP which is undermined by HSV-1 protein ICP27. This work presents novel and important findings about how HSV-1 manipulates the host's immune environment for viral replication and discovers details about an important antiviral mechanism.