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

Abstract

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. • Herpes simplex virus 1-encoded UL38 is a STING antagonist • Loss of this UL38 activity made HSV-1 less replicable and pathogenic in vivo • A STING-derived peptide is designed to target the STING-UL38 interface • This peptide shows potent therapeutic efficacy against HSV-1 infection in vivo Wang et al. reveal that herpes simplex virus 1-encoded UL38 is a STING antagonist to evade antiviral immunity by directly binding to STING. They further develop a peptide derived from STING sequence to specifically target the STING-UL38 interface, which shows potent in vivo therapeutic efficacy against this virus.

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