Herpes simplex virus disrupts NF-κB regulation by blocking its recruitment on the IκBα promoter and directing the factor on viral genes

Abstract Herpes simplex viruses (HSVs) are able to hijack the host-cell IκB kinase (IKK)/NF-κB pathway, which regulates critical cell functions from apoptosis to inflammatory responses; however, the molecular mechanisms involved and the outcome of the signaling dysregulation on the host-virus interaction are mostly unknown. Here we show that in human keratinocytes HSV-1 attains a sophisticated control of the IKK/NF-κB pathway, inducing two distinct temporally controlled waves of IKK activity and disrupting the NF-κB autoregulatory mechanism. Using chromatin immunoprecipitation we demonstrate that dysregulation of the NF-κB-response is mediated by a virus-induced block of NF-κB recruitment to the promoter of the IκBα gene, encoding the main NF-κB-inhibitor. We also show that HSV-1 redirects NF-κB recruitment to the promoter of ICP0, an immediate-early viral gene with a key role in promoting virus replication. The results reveal a new level of control of cellular functions by invading viruses and suggest that persistent NF-κB activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication.