HTLV-I is implicated with adult T-cell leukemia and certain other clinical disorders. The viral Tax protein is regarded as a key element in HTLV-I pathogenicity due to its ability to activate a wide variety of cellular regulatory factors. As such, Tax may likely activate also latent infection of certain other pathogenic viruses whose expression is modulated by cellular transcription factors. Therefore, investigation of Tax effect on the expression of these viruses is of particular clinical importance, since HTLV-I infection of carriers harboring such latent viruses may trigger their related diseases. In this study we focused on simian virus 40 and demonstrated that Tax activates the promoter of this virus through NF-kappaB-associated pathway. Furthermore, we show that this activation requires an interaction of the NF-kappaB factor p65(RelA) with CBP, which depends on PKA-mediated phosphorylation of p65(RelA). Finally, the present study proves that the nuclear Tax plays a critical role in Tax-induced NF-kappaB-mediated SV40 activation.