The major immediate-early proteins of human cytomegalovirus (HCMV) play a pivotal role in controlling viral and cellular gene expression during productive infection. As well as negatively autoregulating its own promoter, the HCMV 86-kDa major immediate early protein (IE86) activates viral early gene expression and is known to be a promiscuous transcriptional regulator of cellular genes. IE86 appears to act as a multimodal transcription factor. It is able to bind directly to target promoters to activate transcription but is also able to bridge between upstream binding factors such as CREB/ATF and the basal transcription complex as well as interacting directly with general transcription factors such as TATA-binding protein and TFIIB. We now show that IE86 is also able to interact directly with histone acetyltransferases during infection. At least one of these factors is the histone acetyltransferase CBP-associated factor (P/CAF). Furthermore, we show that this interaction results in synergistic transactivation by IE86 of IE86-responsive promoters. Recruitment of such chromatin-remodeling factors to target promoters by IE86 may help explain the ability of this viral protein to act as a promiscuous transactivator of cellular genes.Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which rarely causes disease upon primary infection and remains latent in the infected host throughout its life (54). Infection usually becomes clinically apparent only in the newborn or immunocompromised upon primary infection or reactivation (67). As with all herpesviruses, productive infection with HCMV results in a regulated cascade of viral gene expression which has been operationally defined as immediateearly (IE), early (E), and late (L) (17,53,78,88,89).IE proteins are expressed in the absence of de novo protein synthesis, and the major IE proteins (IE72 and IE86) result from differential splicing of the major IE region (29,32,77,79,87). IE72 and IE86 are known to transactivate E and L genes (1,38,50,70,71) and either positively or negatively autoregulate their own expression (10,11,28,45,62,76). While IE72 is able to weakly activate some cellular promoters, IE86 is a strong transcriptional activator of cellular gene expression (6,15,25,26,31,40,48,51,55,85) and appears to be able to act at the promoter level by a number of mechanisms. It is able to bind DNA directly so repressing its own promoter (12,28,30,33,35,44,45,49,60,95) and has recently been shown to bind directly to at least one cellular promoter region, resulting in transcriptional activation (5). Similarly, IE86 has been shown to bind to a number of cellular factors (6,19,24,36,42,47,48,69,73,74,97), suggesting that IE86 may also act by bridging between transcription factors bound upstream of the basal promoter and the transcription preinitiation complex. IE86 is also able to directly activate basal promoter elements containing only a TATA motif, and this may result from the ability of IE86 to interact directly with general transcription factors such as TFIIB and T...