The molecular basis of the inhibition of HTLV-2 retroviral replication by the MHC class II transactivator (CIITA)

The transcriptional activator CIITA is the master regulator of the
expression ofMHC class II genes. In addition to this major role, we
found that CIITA exerts an important inhibitory effect on the
HTLV-2 replication. This inhibition is mediated by the N-terminal
1–321 region where we identified a minimal fragment of 80 aminoacids that specifically blocks the activity of the viral transactivator Tax2. To unveil the biochemical basis of the CIITA-mediated inhibition of Tax2 we first focussed on the identification of the cellular cofactors used by Tax2 to transactivate the viral promoter.
Preliminary data indicate that the transactivation activity of Tax2
and Tax1, the HTLV-1 homologous of Tax2, is differently influenced
by the hystone acetyltransferases CBP, p300 and PCAF
providing new informations on the biology of HTLV-2.
Furthermore, none of these factors was able to reverse the inhibitory
action of CIITA on Tax2 function. Interestingly, we found that the
B and, to a lesser extent, the A subunits of the NFY complex inhibit
Tax2 activity when iper-expressed in cells. On the basis of our results
and of the reported physical interactions between NFY and both
CIITA and Tax1, a possible mechanism for the CIITA-mediated
inhibition of Tax2 activity would be the binding of the CIITA-NFY
complex to Tax2. When expressed in cells, CIITA interacts with the
NFY complex; this interaction changes the conformation of NFY
increasing its binding affinity for Tax2. Following this model the
inhibition of Tax2 by CIITA it is not due to the squelching of a
transcriptional positive co-activator, but instead to the recruitment
of a cellular factor, NFY, with a negative regulatory action on Tax2.
On the whole these results confirm that CIITA may represent a
physiologic tool for novel therapeutic strategies aimed at counteracting
HLTV-2 replication and spreading.