Chen HM, Zhang J, Li JX, Li CH, Li YF, Zhang Q, Kong B, Wang PH

Although non-structural proteins of HPV are known to modulate interferon (IFN) responses, the specific role of HPV16 E4 in immune evasion remains poorly defined. In this study, we demonstrated that HPV16 E4 inhibited IFN and IFN-stimulated gene (ISG) expression induced by VSV, MHV, SeV, HSV1, and HPV16 infection. Plaque assays ...

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revealed that E4-expressing cells produced higher titers of VSV and HSV1, supporting its role in promoting viral replication. Dual-luciferase reporter assays and RT-qPCR analyses confirmed that HPV16 E4 attenuates IFN responses by targeting key antiviral pathways, including RIG-I/MDA5-MAVS, TLR3-TRIF, and cGAS-STING. Coimmunoprecipitation and immunoblotting assays revealed that E4 interacted with RIG-I, MDA5, MAVS, TRIF, TBK1, and IRF3, thereby inhibiting the phosphorylation of TBK1 and IRF3. Confocal microscopy and nuclear-cytoplasmic fractionation demonstrated that E4 impaired IRF3 nuclear translocation, a pivotal step in IFN signaling. E4 also suppressed the JAK-STAT pathway, resulting in reduced ISG expression. Furthermore, E4 disrupted ISGF3 complex formation by interacting with STAT2 and IRF9, thereby preventing the nuclear translocation of STAT1, STAT2, and IRF9. Collectively, these mechanisms facilitate viral replication and enable evasion of host antiviral immunity. These findings advance our understanding of HPV immune evasion strategies and suggest novel therapeutic targets for managing HPV-related diseases.

Date: Jun. 01, 2025

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