153 Insight into the molecular mechanism of CIITA-mediated inhibition of HIV-1 and HTLV transactivators

Abstract

We previously showed that CIITA, the master regulator of MHC-II genes transcription, acts as a potent inhibitor of HIV and HTLV-2 replication by suppressing the activity of their respective viral transactivators Tat and Tax-2. Here we show that CIITA inhibits also the activity of Tax-1 the transcriptional activator of HTLV-1, the aetiological agent of Adult T cell Leukemia (ATL). Interestingly, both Tax-2 and Tax-1 are inhibited by the same region of CIITA that we have now restricted to 60 aa at the N-term of the molecule. This region is distinct from the one inhibiting the HIV-1 Tat transactivator. Thus, our hypothesis is that Tax-1 and Tax-2 transactivators are inhibited through a common molecular mechanism which is different from the one inhibiting HIV-1 replication. Our previous results have shown that another transcription factor, NF-Y, which cooperates with CIITA in the activation of MHC-II genes transcription, inhibits Tax-2 activity when over expressed in cells. A similar effect is observed also with Tax-1 and we are assessing whether NF-Y is involved in CIITA-mediated inhibition of Tax-1 and Tax-2. We show that Tax-1 interacts with NF-YB subunit and report on a new interaction between CIITA and both Tax-1 and Tax-2 in vivo. Studies are also in progress to determine whether the suppressive effect of CIITA on Tax-1 correlates with the inhibition of HLTV-1 replication as well. These findings reveal that CIITA, beside its well known role in adaptive immunity has an important function in innate immunity, counteracting retrovirus replication and spreading.