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

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.

Grant Number: 5P01AI127335-09
NIH Institute/Center: NIH
Principal Investigator: Patrizia Caposio