The MHC-II Transactivator CIITA, a Viral Restriction Factor Targeting Human T-Cell Lymphotropic Virus Type 1 Tax-1 Function and Inhibiting Viral Replication

Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of Adult T cell Leukemia-Lymphoma (ATLL). The viral transactivator Tax-1 protein plays a key role in the pathiogenesis of ATLL. We demonstrate that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of 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 via the first 108 aminoacids of Tax-1 and two CIITA adjacent regions (1-252 and 253-410). Interestingly only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64-124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired 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 ATF1 restored Tax-1-dependent transactivation of the viral LTR promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading