Herpes Simplex Virus Type 2 Blocks IFN-β Production through the Viral UL24 N-Terminal Domain-Mediated Inhibition of IRF-3 Phosphorylation.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101509722 Publication Model: Electronic Cited Medium: Internet ISSN: 1999-4915 (Electronic) Linking ISSN: 19994915 NLM ISO Abbreviation: Viruses Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI
    • Subject Terms:
      Herpesvirus 2, Human*/genetics ; Herpesvirus 2, Human*/immunology ; Herpesvirus 2, Human*/physiology ; Interferon-beta*/metabolism ; Interferon-beta*/genetics ; Interferon Regulatory Factor-3*/metabolism ; Interferon Regulatory Factor-3*/genetics; Humans ; Phosphorylation ; Viral Proteins/metabolism ; Viral Proteins/genetics ; Promoter Regions, Genetic ; Immune Evasion ; Animals ; Signal Transduction ; HEK293 Cells ; Chlorocebus aethiops ; Cell Line ; Host-Pathogen Interactions ; Vero Cells
    • Abstract:
      Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus, the cause of genital herpes, and its infection can increase the risk of HIV-1 infection. After initial infection, HSV-2 can establish lifelong latency within the nervous system, which is likely associated with the virus-mediated immune evasion. In this study, we found that HSV-2 UL24 significantly inhibited the activation of the IFN-β promoter and the production of IFN-β at both mRNA and protein levels. Of importance, the inhibitory effect of HSV-2 on IFN-β production was significantly impaired in the context of HSV-2 infection when UL24 was knocked down. Additional studies revealed that, although the full-length HSV-2 UL24 affected cell cycle and viability to some extent, its N-terminal 1-202AA domain showed no obvious cytotoxicity while its C-terminal 201-281 AA domain had a minimal impact on cell viability. Further studies showed that the N-terminal 1-202 AA domain of HSV-2 UL24 (HSV-2 UL24-N) was the main functional region responsible for the inhibition of IFN-β production mediated by HSV-2 UL24. This domain significantly suppressed the activity of RIG-IN, MAVS, TBK-1, IKK-ε, or the IRF-3/5D-activated IFN-β promoter. Mechanistically, HSV-2 UL24-N suppressed IRF-3 phosphorylation, resulting in the inhibition of IFN-β production. The findings of this study highlight the significance of HSV-2 UL24 in inhibiting IFN-β production, revealing two potential roles of UL24 during HSV-2 infection: facilitating immune evasion and inducing cell cycle arrest.
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    • Grant Information:
      82171736 National Natural Science Foundation of China
    • Contributed Indexing:
      Keywords: HSV-2; IFN-β; IRF-3; UL24; immune evasion
    • Accession Number:
      77238-31-4 (Interferon-beta)
      0 (Interferon Regulatory Factor-3)
      0 (IRF3 protein, human)
      0 (Viral Proteins)
    • Publication Date:
      Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241104
    • Publication Date:
      20241105
    • Accession Number:
      PMC11512255
    • Accession Number:
      10.3390/v16101601
    • Accession Number:
      39459934