Role of HCMV UL7-8 genes in the regulation of host cell signaling during viral latency and reactivation

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SUMMARY – PROJECT 4 Human cytomegalovirus (HCMV) is a -herpesvirus infecting 44-100% of the population and remains a significant cause of morbidity and mortality in solid organ transplant (SOT) and allogeneic hematopoietic stem cell transplant (SCT) recipients. We previously demonstrated that HCMV RL11 gene UL7 targets signaling pathways involved in cellular differentiation that are important for viral reactivation and hematopoiesis. We recently found that another RL11 gene, UL8, expressed from the spliced UL7 transcript, is required for viral reactivation. pUL8 shares the same N-terminal Ig-like domain with pUL7, with a longer stalk domain and a distinctive cytoplasmic tail. Using a proximity sensor approach to identify UL8 interactome in HEK293 transfected cells, we identified proteins in the RhoA, Wnt, and EGFR pathways. Moreover, our preliminary data shows that pUL7 binds to UL8 and enhances UL8-mediated non-canonical Wnt pathway via Rho A. We hypothesize that UL8 signaling is important for viral reactivation and the interaction between UL7 and UL8 shapes the intracellular events conducive to CD34+ HPCs differentiation and dissemination into the host tissues. Therefore, in SA1 we will define and functionally characterize the UL8 interactome in the contest of HCMV infection. In SA2 we will focus on the cellular signaling shaped by UL7 and UL8 and how this impact latency and reactivation. Finally based on our recently publication on FOXO3 inactivation by UL7, HCMV miR-UL112-3p and -US5-1 and protection from apoptosis as well as preliminary data suggesting an involvement of UL8 and several HCMV miRNA in promoting survival of HCMV CD34+ HPC infected cells, we propose in SA3 to investigate the mechanisms of FOXOs inactivation by UL7-8 and HCMV miRNAs and the impact on apoptosis and establishment of latency.