title: Major histocompatibility complex class II transactivator CIITA is a viral restriction factor that targets human T-cell lymphotropic virus type 1 Tax-1 function and inhibits viral replication.
abstract: Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex 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 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 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 coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral long-terminal-repeat 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.
authors.affiliation: Department of Experimental Medicine, University of Insubria, Via O. Rossi 9, Varese 21100, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosi
authors.forename: Greta
authors.initials: G
authors.lastname: Forlani
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andresen
authors.forename: Marco
authors.initials: M
authors.lastname: Turci
authors.forename: Umberto
authors.initials: U
authors.lastname: Bertazzoni
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.forename: Guido
authors.initials: G
authors.lastname: Poli
authors.forename: Roberto S
authors.initials: RS
authors.lastname: Accolla
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D016356:Gene Products, tax / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000821:virology; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015534:Trans-Activators / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D016356:Gene Products, tax; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; C514970:tax protein, Human T-lymphotrophic virus 1