Human Cytomegalovirus Binding to Human Monocytes Induces Immunoregulatory Gene Expression

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Abstract
To continue our investigation of the cellular events that occur following human CMV (HCMV) infection, we focused on the regulation of cellular activation following viral binding to human monocytes. First, we showed that viral binding induced a number of immunoregulatory genes (IL-1β, A20, NF-κB-p105/p50, and IκBα) in unactivated monocytes and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55) and gH (UL75), inhibited the induction of these genes. Next, we demonstrated that these viral ligands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors. We then investigated if HCMV binding also resulted in the translation and secretion of cytokines. Our results showed that HCMV binding to monocytes resulted in the production and release of IL-1β protein. Because these induced gene products have NF-κB sites in their promoter regions, we next examined whether there was an up-regulation of nuclear NF-κB levels. These experiments showed that, in fact, NF-κB was translocated to the nucleus following viral binding or purified viral ligand binding. Changes in IκBα levels correlated with the changes in NF-κB translocation. Lastly, we demonstrated that p38 kinase activity played a central role in IL-1β production and that it was rapidly up-regulated following infection. These results support our hypothesis that HCMV initiates a signal transduction pathway that leads to monocyte activation and pinpoints a potential mechanism whereby HCMV infection of monocytes can result in profound pathogenesis, especially in chronic inflammatory-type conditions.