Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many evidences have shown that constitutive activation of NF-kB pathway by Tax-1 is crucial for T-cell transformation. We demonstrate that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the function of the viral transactivator Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo. CIITA residues from positions 64-124 are required to block Tax-1 transactivation and this inhibitory action correlates with the nuclear localization of CIITA. CIITA severely impairs the physical and functional interaction of Tax-1 with the cellular co-activators PCAF, CREB and ATF1, which are required for the optimal activation of HTLV-1 promoter. Accordingly, the over-expression of PCAF, CREB and ATF1restore Tax-1-dependent transactivation of the viral LTR promoter inhibited by CIITA. Interestingly, CIITA inhibits also Tax-1-mediated activation of the NF-kB pathway, suggesting that its newly discovered function as viral restriction factor in HTLV-1 infection may also result in a suppression of Tax-1-induced cellular transformation. Thus, assessing the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential.
(C) 2013 Lippincott Williams & Wilkins, Inc.