Plant immune responses to pathogen infection require the elaborate transcriptome reprogramming. Histone acetylation is known to play important roles during host-pathogen interactions. However, how plants employ these processes against viral infections remains largely unknown. Here, we discovered that hyperacetylation/hypoacetylation of histone H3 can inhibit/enhance Chinese Wheat Mosaic Virus (CWMV) infection in wheat, and confirmed that TaSRT2 interacts with P153. The TaSRT2-P153 interaction prevents the shuttling of TaSRT2 from the cytoplasm into the nucleus, and this restricts TaSRT2 deacetylation of H3K9ac and H3K79ac, allowing the modulation of TaSRT2-mediated immune responses such as the induction expression of resistance-related genes to intensify the plant basal defense against the CWMV infection. Importantly, the 322 to 332 amino acids in TaSRT2 influenced the interaction between TaSRT2 and P153. Our results discover an effective immune mechanism by which SRT2 interacts with viral proteins to activate the host basal resistance through inhibiting the function of deacetylases during viral infection.