Characterization of the human cytomegalovirus irs1 and trs1 genes: a second immediate-early transcription unit within irs1 whose product antagonizes transcriptional activation.

We have characterized the irs1 and trs1 genes of human cytomegalovirus. The previously identified mRNAs as well as their corresponding protein products pIRS1 and pTRS1 could be detected during all phases of the viral replication cycle. The proteins were present in the nucleus and cytoplasm during the immediate-early and early phases of the viral growth cycle but were predominantly cytoplasmic late after infection. Although pIRS1 and pTRS1 exhibited little transcriptional activation potential on their own, both cooperated with the IE1 and IE2 proteins to enhance expression from a variety of viral promoters. We have also identified a previously undescribed immediate-early gene product encoded within the irs1 gene that we have termed pIRS1(263). This new protein is encoded within the 3' end of the irs1 gene and is in the same reading frame as the large pIRS1 protein. Expression of the irs1(263) gene is controlled by a promoter that resides within the irs1 open reading frame in the unique short region of the viral genome. pIRS1(263) resides in the nucleus and antagonizes transcriptional activation by cytomegalovirus immediate-early proteins. We propose that pIRS1(263), whose promoter responds to immediate-early transcriptional activators, serves as part of a regulatory loop, antagonizing the function of the viral proteins that are responsible for its synthesis.