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

Abstract

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 de novo produced intracellular 2-3cGAMP, but also extracellular 2-3cGAMP activates the STING pathway by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this signaling molecule. We hypothesized that the import of exogenous 2-3cGAMP functions to establish an antiviral state like that seen with the paracrine antiviral activities of interferon. Further, to establish a successful infection, HSV-1 must undermine this induction of the STING pathway by inhibiting the biological functions of SLC19A1. Herein, we report that treatment of the monocytic cell line, THP-1 cells, epithelial cells (ARPE-19) and SH-SY5Y neuronal cell line with exogenous 2-3cGAMP induces interferon production and establishes an antiviral state. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2-3cGAMP-induced antiviral state. Additionally, 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 2-3cGAMP which is undermined by HSV-1. This work presents novel and important findings about how HSV-1 manipulates the hosts immune environment for viral replication and discovers details about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future. ImportanceHSV-1 has evolved multiple mechanisms to neutralize of the hosts innate and intrinsic defense pathways, such as the STING pathway. Here, we identified an antiviral response in which extracellular 2-3cGAMP 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 2-3cGAMP 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 hosts 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.