Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells

Abstract

Infection with human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortalityfollowing hematopoietic stem cell transplant (HSCT)because of various hematologic problems, includingmyelosuppression. Here, we demonstrate that latently expressed HCMV miR-US5-2 downregulates the transcriptional repressor NGFI-A binding protein(NAB1) to induce myelosuppression of uninfected CD34+ hematopoietic progenitor cells (HPCs) through an increase in TGF-β production. Infection of HPCs with an HCMVΔmiR-US5-2 mutant resulted in decreased TGF-β expression and restoration of myelopoiesis. In contrast, we show that infected HPCs are refractory to TGF-β signaling as another HCMV miRNA, miR-UL22A, downregulates SMAD3, which is required for maintenance of latency. Our data suggest that latently expressed viral miRNAs manipulate stem cell homeostasis by inducing secretion of TGF-β while protecting infected HPCs from TGF-β-mediated effects on viral latency and reactivation. These observations provide a mechanism through which HCMV induces global myelosuppression following HSCT while maintaining lifelong infection in myeloid lineage cells.