Myeloid dendritic cells repress human cytomegalovirus gene expression and spread by releasing interferon-unrelated soluble antiviral factors.

Abstract

Cytomegalovirus (CMV) is a beta-herpesvirus that latently infects most adult humans worldwide and is a major cause of morbidity and mortality in immunocompromised hosts. Latent human CMV (HCMV) is believed to reside in precursors of myeloid-lineage, leukocytes and monocytes, which give raise to macrophages and dendritic cells. We report here that human monocyte derived DCs (mo-DC) suppress HCMV infection in coculture with infected fibroblasts target cells in an effector-to-target-ratio dependent manner. Intriguingly, optimal activation of mo-DC was achieved in coculture conditions, not by their direct infection with HCMV, implying that mo-DC may recognize unique molecular patterns on, or within, infected fibroblasts. We show that HCMV is controlled by secreted factors that act by priming defenses in target cells rather than by direct viral neutralization, but we excluded a role for IFNs in this control. The expression of lytic viral genes in infected cells and the progression of infection were significantly slowed down, but this effect was reversible, indicating that the control of infection depended on the transient induction of antiviral effector molecules in target cells. Using immediate-early or late-phase reporter HCMVs, we show that soluble factors secreted in the cocultures suppress HCMV replication at both stages of the infection and that their antiviral effect is robust and comparable in numerous batches of mo-DCs as well as in primary fibroblasts and stromal cells.Importance Human cytomegalovirus is a widespread opportunistic pathogen that can cause severe disease and complications in vulnerable individuals. This includes newborn children, HIV AIDS patients or transplant recipients. Although the majority of healthy humans carry this virus throughout their lives without symptoms, it is not exactly clear which tissues in the body are the main reservoirs of latent virus infection, or how the delicate balance between the virus and the immune system is maintained over the individual's lifetime. Here for the first time, we provide evidence for a novel mechanism of direct virus control by a subset of human innate immune cells called Dendritic Cells, which are regarded as a major site of virus latency and reactivation. Our findings may have important implications in HCMV disease prevention as well as development of novel therapeutic approaches.