Herpes Simplex Virus 1 γ ₁ 34.5 Protein Inhibits STING Activation That Restricts Viral Replication

Abstract

The γ34.5 gene of herpes simplex virus 1 (HSV-1) encodes a virulence factor that promotes viral pathogenesis. Although it perturbs TANK-binding kinase 1 (TBK1) in the complex network of innate immune pathways, the underlying mechanism is obscure. Here we report that HSV-1 γ34.5 targets stimulator of interferon genes (STING) in the intracellular DNA recognition pathway that regulates TBK1 activation. In virus-infected cells the γ34.5 protein associates with and inactivates STING, which leads to downregulation of interferon regulatory factor 3 (IRF3) and IFN responses. Importantly, HSV-1 γ34.5 disrupts translocation of STING from the endoplasmic reticulum to Golgi apparatus, a process necessary to prime cellular immunity. Deletion of γ34.5 or its amino-terminal domain from HSV-1 abolishes the observed inhibitory activities. Consistently, an HSV mutant that lacks functional γ34.5 replicated less efficiently in STING than in STING mouse embryonic fibroblasts. Moreover, reconstituted expression of human STING in the STING cells activated IRF3 and reduced viral growth. These results suggest that control of the DNA sensing pathway by γ34.5 is advantageous to HSV infection. Viral inhibition of innate immunity contributes to herpes simplex virus pathogenesis. Although this complex process involves multiple factors, the underlying events remain unclear. We demonstrate that an HSV virulence factor γ34.5 precludes the activation of STING, a central adaptor in the intracellular DNA sensing pathway. Upon HSV infection, this viral protein engages with and inactivates STING. Consequently, it compromises host immunity and facilitates HSV replication. These observations uncover an HSV mechanism that is likely to mediate viral virulence.

Cytosolic DNA‐sensing immune response and viral infection

“…In addition to the viral serine protease of HSV‐1, VP24, some viral tegument proteins, such as UL24 and UL36, have evolved certain strategies to target IRF3 and NF‐κB by negatively regulating them . Interestingly, it has been demonstrated that the γ34.5 gene of HSV‐1 encodes a virulence factor for HSV‐1‐mediated pathogenesis that may also act as an antagonistic factor against the cGAS/STING pathway , which is consistent with the finding that an HSV‐1 mutant in which the γ34.5 gene has been deleted no longer exhibits an antagonistic function in infected cells, thereby facilitating IFN production in a STING‐dependent manner . On the other hand, an oncogenic herpesvirus, KHSV, which encodes viral interferon regulatory factor 1 gene, has been shown to prevent an association between STING and TBK1, thereby inhibiting initiation of IRF3‐mediated signal activation .…”

Replicative conditioning of Herpes simplex type 1 virus by Survivin promoter, combined to ERBB2 retargeting, improves tumour cell-restricted oncolysis

“…To date, attenuation by gene-inactivating deletions has been widely applied to HSV-1, but this strategy can limit the efficacy of oHSVs since it can compromise the virulence also in tumour cells 54 , and affect the viral ability to escape host's antiviral immune pathways (e.g. cGAS/STING axis) 55,56 .…”

Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells

“…Consistently, ΔN146 induced phosphorylation of IRF3 upon infection of 4T1 and MDA-MB-231 cells. This is attributable to the deletion in the N-terminal domain from ␥ 1 34.5 necessary to inhibit STING or TBK1 (18,53). The immunostimulatory activity, coupled with its robust replication in tumor cells, suggests that ΔN146 is a unique oncolytic platform.…”