The Race between Host Antiviral Innate Immunity and the Immune Evasion Strategies of Herpes Simplex Virus 1

Abstract

Herpes simplex virus 1 (HSV-1) is very successful in establishing acute and latent infections in humans by counteracting host antiviral innate immune responses. HSV-1 has evolved various strategies to evade host antiviral innate immunity and some cellular survival-associated pathways. Since there is still no vaccine available for HSV-1, a continuous update of information regarding the interaction between HSV-1 infection and the host antiviral innate immunity will provide novel insights to develop new therapeutic strategies for HSV-1 infection and its associated diseases. Here, we update recent studies about how HSV-1 evades the host antiviral innate immunity, specifically how HSV-1 proteins directly or indirectly target the adaptors in the antiviral innate immunity signaling pathways to downregulate the signal transduction. Additionally, some classical intracellular stress responses, which also play important roles in defense of viral invasion, will be discussed here. With a comprehensive review of evasion mechanisms of antiviral innate immunity by HSV-1, we will be able to develop potential new targets for therapies and a possible vaccine against HSV-1 infections.

Keywords: DDR; NLR; RIG-I/MDA5; TLR; antiviral immunity; apoptosis; cGAS-STING; herpes simplex virus; immune evasion.

FIG 1

HSV-1-mediated evasion of the RLR and TLR signaling pathway. TLRs are located at both the plasma membrane and endosomes. They sense different ligands like viral dsRNA, dsDNA, and glycoproteins; transduce signals through TRIF and MyD88; and then lead the activation of IRFs and NF-κB. RIG-I and MDA5 detect distinct RNA structures and signal through the adaptor protein MAVS protein to trigger IRF3 and NF-κB activation. The IFN-I and inflammatory cytokines are induced for antiviral immunity. HSV-1 proteins can hijack multiple steps downstream of RLR and TLR signaling pathways. Solid lines indicate confirmed interactions between adaptors and HSV-1 proteins. Dashed lines indicate uncertain interactions or that the underlying mechanism is unknown. CBP, CREB-binding protein; P, phosphate; U, ubiquitin.

FIG 2

Evasion of the DNA sensor-mediated IFN-I signaling pathway by HSV-1. Cytosolic DNA sensors, such as cGAS, IFI16, DDX41, and DAI, recognize double-stranded DNA in the cytosol and trigger IFN-I production through the transmission of a series of signals. Multiple steps in the DNA-sensing signaling pathway can be targeted by HSV-1 proteins, including both DNA sensor-mediated viral recognition and subsequent signaling. Many adaptors and transcription factors further downstream in the DNA sensor-mediated signaling pathway, such as TBK1, IRF3, p65, and p50, are shared by the RLR-mediated IFN-I signaling pathway. Therefore, it is plausible to consider that viral proteins targeting these molecules in the RLR-mediated signaling pathway may inhibit cytosolic DNA-sensing signals through a similar mechanism. Solid lines indicate confirmed interactions between adaptors and HSV-1 proteins. Dashed lines indicate uncertain interactions or that the underlying mechanism is not known. CBP, CREB-binding protein; P, phosphate; U, ubiquitin. (Based on data from reference .)

FIG 3

HSV-1-mediated evasion of the IFNAR-JAK-STAT signaling pathway. The antiviral activities of IFN-I are initiated by binding to their cognate receptor IFNAR1 and IFNAR2 to trigger a signaling cascade, namely, JAK-STAT pathways. Viral proteins from HSV-1 interact with adaptors to block the signal transduction, and some proteins target ISGs directly for evasion of host antiviral immunity. Dashed lines indicate uncertain interactions that need to be studied further, or the underlying mechanism is unknown. P, phosphate.

FIG 4

HSV-1 evades DDR, ER stress, autophagy, stress granules (SGs), and apoptosis. HSV-1 infection could elicit some other immune responses like SGs, ER stress, apoptosis, DDR, and autophagy that contribute to restricting viral infection. However, these immune responses are also manipulated by viral proteins. Solid lines indicate confirmed interactions between adaptors and HSV-1 proteins. P, phosphate; U, ubiquitin.