231 The MHC Class II Transactivator, CIITA, is a Viral Restriction Factor for Human Oncogenic Retroviruses

We show that CIITA, the master regulator of MHC-II gene expression, inhibits the replication of HTLV-1 by targeting the viral transactivator Tax-1. CIITA and Tax-1 physically interact in vivo and the first 108 aminoacids of Tax-1 are necessary for this binding. Two adjacent regions (1-252 and 253-410) of CIITA bind independently to Tax-1, but only region 1-252 mediates Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64-124 are required to block Tax-1 transactivation. The CIITA inhibitory action on Tax-1 function correlates with the nuclear localization of CIITA and is independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of HTLV-2 Tax-2. CIITA severely impairs the physical and functional interaction of Tax-1 with the cellular co-activator PCAF, which is required for the optimal activation of HTLV-1 promoter. Accordingly, CIITA-inhibited transactivation of the viral LTR promoter by Tax-1, is rescued by the over-expression of PCAF. Together with the previously reported inhibition of two other human retroviruses, HIV-1 and HTLV-2, these findings support the idea that CIITA might have evolved as a general defense mechanism of the host against retroviruses, not only because it activates the immune response against the infectious agents, but also because of its intrinsic capacity to act as an endogenous viral restriction factor. This investigation was supported by University of Insubria “FAR” to GT; I.S.S. National Research Project on A.I.D.S. n° 40F.1 and 45G.1 to R.S.A.; Fondazione Cariplo grant 2008-2230 and AIRC, grant IG 8862 to R.S.A.