Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency and reactivation

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SUMMARY - OVERALL Human Cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients who often exhibit myelosuppression associated with virus infection. CD34+ Hematopoietic Progenitor Cells (HPCs) are a critical reservoir of latent HCMV that upon cytokine and growth factor signals differentiate into monocytes that further differentiate into macrophages activating production of infectious virus in tissues. Epidermal Growth Factor Receptor (EGFR) signaling pathways in CD34+ HPCs are critical not only for determining HCMV latency and reactivation but also for regulating progenitor cell homeostasis and hematopoiesis. Over the past 3.5 years we have identified critical EGFR signaling pathways regulated by UL138, UL136, UL135, US28, UL7, UL8, and multiple HCMV miRNAs that are important to maintain latency or induce viral reactivation. Most of these pathways are integrally linked with CD34+ HPC proliferation for maintenance of the progenitor cell in the bone marrow niche as well as myelopoiesis. We have shown that multiple HCMV miRNAs synergistically or antagonistically work together with HCMV proteins to regulate these signaling pathways necessary for latency or viral reactivation. In addition, we have observed that UL138 is associated with proteins involved in STAT1 signaling and that HCMV miRNAs target some of these factors. We hypothesize that UL138-WDR48-USP1 and -USP12 interactions along with US28 and the HCMV miRNAs regulate a STAT1 and AKT response to suppress virus replication for latency. We have also shown that US28 signaling induced by chemokines regulate latency or reactivation and is ligand specific. Additionally, we have observed that US28 activation of RhoA is highly regulated by HCMV miRNAs as well as UL8 signaling through the non-canonical Wnt pathway. We hypothesize that MEK/ERK signaling is essential to maintain latency while activation of the RhoA pathway is necessary for reactivation. While the current HCMV PPG has focused on identification of UL138, UL136, UL135, US28, UL7, and viral miRNA EGFR signaling targets, the proposed renewal will focus on how the different HCMV genes interact with one another to regulate these pathways and how they control the virus life cycle. The complexity of signaling events and approaches to comprehensively address questions on viral latency and hematopoiesis can only be achieved through a collaborative effort under a PPG mechanism. Therefore we propose five highly integrated research projects (Project 1: UL133/8 regulation of host cell signaling in viral latency and reactivation; Project 2: miRNA regulation of host cell signaling in viral latency and reactivation; Project 3: US28 regulation of host cell signaling in viral latency and reactivation; Project 4: UL7-8 regulation of host cell signaling in viral latency and reactivation; Project 5: HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation), two scientific cores (Humanized Mouse Core; Biostatistics and Bioinformatics Core) to service these projects, and an Administrative Core to oversee and coordinate the entire program.