Herpes simplex virus 1 encodes a STING antagonist that can be therapeutically targeted.

Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that causes serious symptoms and is known for its strong interactions with host immunity. Here, we revealed that the HSV-1-encoded UL38 is a stimulator of interferon genes (STING) antagonist that interacts with STING to abrogate the STING-TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) interaction, thereby suppressing cyclic GMP-AMP synthase (cGAS)-STING-dependent immune signaling. Losing UL38's STING antagonist activity made HSV-1 incapable of immune evasion and less replicable and pathogenic in vivo. Moreover, on the basis of the UL38-interacting sequence within STING, we rationally designed a series of peptides to target the STING-UL38 interface of UL38 specifically. Among them, a peptide effectively disrupts the STING-UL38 interaction, which unlocks the UL38-suppressed immune response and shows potent therapeutic efficacy against HSV-1 infection in vivo. Therefore, our findings demonstrate that HSV-1 UL38 is a STING antagonist, and targeting the activity of UL38 is a promising strategy for the development of antivirals against this notorious virus.