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 longterminal-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.

The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

“…In the phRL-CMV vector (Promega), the expression of Renilla luciferase is under the control of the cytomegalovirus promoter. The pCMV-Tax-1 and Tax-2 plasmids were previously described (51,53). The pACH plasmid, containing the entire HTLV-1 genome, has been previously described (53).…”

“…The pCMV-Tax-1 and Tax-2 plasmids were previously described (51,53). The pACH plasmid, containing the entire HTLV-1 genome, has been previously described (53). Expression vectors for FLAG-tagged full-length (amino acids 1 to 1130) CIITA (pcfCIITA) and for the deletion-containing forms of CIITA (pcf1-252, pcf253-1130, pcf253-410, pcf⌬253-410, pcf64-200) have been described elsewhere (51,53,61).…”

“…Importantly, this inhibition correlates with the suppression of HTLV-1 and HTLV-2 replication, respectively (50)(51)(52)(53)(54). Similarly, we previously found that CIITA also inhibits HIV-1 replication by targeting the viral transactivator Tat (55,56).…”

“…Importantly, CIITA may be expressed in activated human T cells, the specific targets of HTLV-1. Thus, CIITA is an example of a versatile molecule able to counteract retroviral infections in a dual manner, not only because of its capacity to trigger the adaptive immune response against pathogens but also for its intrinsic antiviral properties that enable it to act as a bona fide viral restriction factor (53,60).…”

Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure

“…Indeed, the ability to shuttle appears to be a common feature among NLR family members. For example, CIITA (NLRA) and NLRC5 have the ability to shuttle from the cytosol to the nucleus to modulate the host-antivirus response or following stimulation with virus-associated PAMPs (Benko et al, 2010;Meissner et al, 2010;Orlandi et al, 2011;Tosi et al, 2011). Likewise, both NOD1 and NOD2 have been shown to shuttle from the cytosol to the plasma membrane, where membrane association has been linked to function (Kufer et al, 2008).…”