The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1

Enigmatic mechanisms restore the resting state in activated lymphocytes fol lowing human immunodeficiency virus type 1 (HIV-1) infection, rarely allowi ng persistent nonproductive infection. We detail a mechanism whereby cellul ar factors could establish virological latency. The transcription factors Y Y1 and LSF cooperate in repression of transcription from the HIV-1 long ter minal repeat (LTR). LSF recruits YY1 to the LTR via the zinc fingers of YY1 . The first two zinc fingers were observed to be sufficient for this intera ction in vitro. A mutant of LSF incapable of binding DNA blocked repression . Like other transcriptional repressors, YY1 can function via recruitment o f histone deacetylase (HDAC). We find that HDAC1 copurifies with the LTR-bi nding YY1-LSF repressor complex, the domain of YY1 that interacts with HDAC 1 is required to repress the HIV-1 promoter, expression of HDAC1 augments r epression of the LTR by YY1, and the deacetylase inhibitor trichostatin A b locks repression mediated by YYI. This novel link between HDAC recruitment and inhibition of HIV-1 expression by YY1 and LSF, in the natural context o f a viral promoter integrated into chromosomal DNA, is the first demonstrat ion of a molecular mechanism of repression of HUV-1. YY1 and LSF may establ ish transcriptional and virological latency of HIV, a state that has recent ly been recognized in vivo and has significant implications for the long-te rm treatment of AIDS.