Transcriptional Control of Human Cytomegalovirus Latency

Abstract HCMV encodes multiple proteins that suppress lytic phase immediate early (IE) transcription during latency. These include Us28 and UL138. We identified a new repressor of the MIEP during latency: the Pentamer. The Pentamer is a five-member glycoprotein complex consisting of gH, gL, UL128, UL130, and UL131 that is required for entry into epithelial and endothelial cells. We determined the Pentamer represses the MIEP during both lytic and latent infections. Provocatively, we determined at least two different Pentamer alleles exist, one that strongly represses the MIEP, and one that weakly represses the MIEP. We hypothesize that HCMV uses unique Pentamer alleles to create different sub-sets of virions pre-programmed to either initiate a lytic infection or to establish latency. To test this hypothesis, in Aim 1 we will create genetically matched virus strains (laboratory and clinical) with pro-lytic or pro-latency Pentamer alleles and test them for their propensity to initiate lytic infection in fibroblasts, epithelial and endothelial cells, to select against Pentamer function during fibroblast propagation, and to establish latency in primary CD34+ cells. In Aim 2 we will determine the mechanism through which the Pentamer represses the MIEP.