Human Cytomegalovirus UL4 is Required for Viral Reactivation via Cellular Reprogramming in Latently Infected CD34+ Progenitor Cells and Humanized Mice

Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality after both solid organ and hematopoietic stem cell transplant, due to bone marrow stem cell engraftment failure, myelosuppression, and immunosuppression. While direct infection and viral replication lead to disease, latent infection in the CD34+ hematopoietic progenitor cell (HPC) pool has direct and indirect effects on hematopoiesis. Studies from several laboratories support the hypothesis that HCMV latency and reactivation are intrinsically linked with the state of the cell. We, and others, have previously demonstrated roles for different viral gene products in regulating both cellular differentiation and the balance between viral latency and reactivation, including the viral RL11 proteins UL7 and UL8. In this study, we show that UL4 is expressed during latency and required for reactivation in HPCs, THP-1 monocytes, and humanized mice. describe both a cell-specific and viral lifecycle-specific role for the RL11 gene UL4 during HCMV infection. Additionally, we demonstrate that UL4 plays specific roles in controlling essential cellular functions including aspects of proliferation and differentiation and immune signaling to assist in establishing a virus-favorable environment in progenitor cells. This study identifies a novel viral reactivation factor that has implications for both viral control and alteration of hematopoiesis in transplant patients.