IRF1 amplifies HSV-1-triggered antiviral innate immunity in a feed-forward manner

Ming Gao; Yining Qi; Junjie Zhang

doi:10.1016/j.cellin.2025.100255

IRF1 amplifies HSV-1-triggered antiviral innate immunity in a feed-forward manner

Cell Insight. 2025 May 22;4(4):100255. doi: 10.1016/j.cellin.2025.100255. eCollection 2025 Aug.

Authors

Ming Gao^{1

2

3}, Yining Qi^{1

2

3}, Junjie Zhang^{1

2

3}

Affiliations

¹ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, State Key Laboratory of Virology and Biosafety, Medical Research Institute, Wuhan University, Wuhan 430071, Hubei, China.
² Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, Hubei, China.
³ Hubei Key Laboratory of Tumor Biological Behavior, Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China.

Abstract

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that establishes lifelong infection and causes a wide range of diseases. Antiviral innate immunity is critical for controlling HSV-1 replication; however, how host cells elicit a full spectrum of antiviral innate immune responses against HSV-1 remains poorly understood. Here, our studies indicate that Interferon regulatory factor 1 (IRF1) amplifies HSV-1-induced antiviral innate immunity in a feed-forward manner. Our data reveal that HSV-1 infection induces IRF1 expression, and MITA/STING contributes to the induction of IRF1 during HSV-1 infection. Moreover, IRF1 restricts HSV-1 replication dependent on its DNA-binding activity. Knockout of IRF1 significantly diminishes the induction of a large subset of interferon-stimulated genes (ISGs) critical for antiviral defense during HSV-1 infection. Notably, IRF1 interacts with IRF3, promoting its recruitment to the promoters of ISGs as well as type I and III interferons, thereby facilitating the activation of antiviral signaling. These findings uncover a novel amplifying role of IRF1 in HSV-1-induced antiviral immunity, which deepens our understanding of innate immune responses against viral infections.

Keywords: Antiviral innate immunity; HSV-1; IRF1; IRF3; MITA; STING.