Maintenance and replication of the human cytomegalovirus genome during latency

Human cytomegalovirus (HCMV) can establish latent infection in hematopoietic progenitor cells (HPCs) or CD14 (+) monocytes. While circularized viral genomes are observed during latency, how viral genomes persist or which viral factors contribute to genome maintenance and/or replication is unclear. Previously, we identified a HCMV cis-acting viral maintenance element (TR element) and showed that HCMV IE1 exon 4 mRNA is expressed in latently infected HPCs. We now show that a smaller IE1 protein species (IE1x4) is expressed in latently infected HPCs. IE1x4 protein expression is required for viral genome persistence and maintenance and replication of a TR element containing plasmid (pTR). Both IE1x4 and the cellular transcription factor Sp1 interact with the TR, and inhibition of Sp1 binding abrogates pTR amplification. Further, IE1x4 interacts with Topoisomerase IIβ (TOPOIIβ), whose activity is required for pTR amplification. These results identify a HCMV latency-specific factor that promotes viral chromosome maintenance and replication.