Abstract
The 86-kilodalton immediate-early (IE) 2 protein (IE2-p86) of human cytomegalovirus (HCMV) is a multifunctional regulator of HCMV gene expression which appears to be essential for triggering the lytic replicative cycle. IE2-p86 functions as a promiscuous transactivator of both viral and cellular gene expression and can repress transcription from its own promoter. In this study we demonstrate that a viral early protein, termed pUL84, which is able to interact with IE2-p86 both in vivo and in vitro, modulates IE2-p86 in a specific manner. First, pUL84 acts as a transdominant inhibitor of IE2-p86-mediated transactivation of both homologous and heterologous promoters. Second, negative autoregulation by IE2-p86 is augmented in the presence of pUL84. Using two in vivo assays, we obtained evidence that expression of pUL84 during the IE phase of the viral replicative cycle leads to an inhibition of viral early gene expression which prevents replication of HCMV and results in a persistent infection of UL84-positive cell lines. Transdominant inhibition of a viral IE function by a protein expressed during the later phases of replication appears to be a novel principle used by herpesviruses which could account for the slow replication of HCMV and may be useful in the development of new antiviral strategies.