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E2 The MHC-II Transactivator CIITA, a Viral Restriction Factor Targeting Human T-Cell Lymphotropic Virus Type 1 Tax-1 Function and Inhibiting Viral Replication

Tosi Giovanna; Forlani, Greta; Andresen, Vibeke; Turci, Marco; Bertazzoni, Umberto; Franchini, Genoveffa; Poli, Guido; Accolla, Roberto S.
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2012
doi: 10.1097/01.qai.0000413809.40640.15

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.

Supported by: Cariplo Foundation 2008-2230, AIRC IG8862, and MIUR 2008-WXF7KK.

© 2012 Lippincott Williams & Wilkins, Inc.