Equine infectious anemia virus blocks interferon responses through Rev-mediated activation of the stress...

Type I interferons (IFNs) play a pivotal role in antiviral defence by inducing interferon-stimulated genes (ISGs) that target multiple stages of viral replication. Equine infectious anemia virus (EIAV) is an ancient lentivirus that establishes long-term asymptomatic infections in equids, suggesting its exceptional immune evasion capabilities. However, the mechanisms by which EIAV modulates IFN responses remain unclear. Here, we demonstrate that EIAV infection attenuates ISG expression at the post-transcriptional level. The viral Rev protein plays a central role by interacting with the stress granule (SG) nucleating protein Ras-GTPase-activating protein binding protein 1 (G3BP1) to induce SG formation. This triggers the phosphorylation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor 2α (eIF2α), which then block the translation of ISGs. Knockdown of G3BP1 or inhibition of PKR activation restores ISGs expression and enhances the antiviral effect of IFN against EIAV. Furthermore, the dimerization and RNA-binding domains of Rev are essential for SG assembly and the subsequent inhibition of IFN responses. Collectively, our findings reveal that EIAV has evolved a unique strategy to evade IFN responses, where the Rev protein reprograms SGs into proviral platforms by suppressing the translation of ISGs.