Human cytomegalovirus microRNAs target the Wnt signaling protein Dishevelled 3 to promote efficient reactivation in CD34+ hematopoietic progenitor cells

Abstract

Human cytomegalovirus (HCMV) establishes latency in CD34+ hematopoietic progenitor cells (HPCs), yet differentiation of these cells promotes viral gene expression and replication. HCMV must therefore precisely regulate the signaling networks that govern HPC fate to maintain latency while preserving the capacity for reactivation. Virally encoded microRNAs (miRNAs) represent powerful tools used by HCMV to manipulate cellular pathways that are involved in HPC fate decisions. Wnt (Wingless/Integrated)/b-catenin signaling represents one such pathway that plays a critical role in regulating both hematopoiesis and virus replication. Previous work determined that HCMV stimulates b-catenin activity during reactivation in CD34+ HPCs. In contrast, here we show that HCMV miRNAs miR-US5-2 and miR-US25-2 downregulate the Wnt pathway adaptor protein Dvl3 during latency and that this downregulation is required for subsequent virus reactivation. These findings support a model of temporally distinct regulation of Wnt pathway components during latency and reactivation.