NF-κB activation can mediate inhibition of human cytomegalovirus replication

Abstract

The activation of NF-κB has long been considered a positive factor for human cytomegalovirus (HCMV) replication. The HCMV immediate-early promoter, the initial transcriptional element in the HCMV replication cycle, is activated by the transcription factor NF-κB, and several HCMV gene products have been demonstrated to activate this transcription factor. However, the role of NF-κB in the full replication cycle of the virus has not been carefully examined. A series of experiments that demonstrate an important inhibitory role of NF-κB for HCMV replication in fibroblasts is presented here. Using both genetic and pharmaceutical methods, it was shown that blocking NF-κB activation in cell culture does not inhibit HCMV replication, but rather leads to a modest increase in replication. Two cytokines inhibitory for HCMV, tumour necrosis factor-α and interferon-γ, no longer inhibit HCMV when NF-κB activation is blocked. Furthermore, forced expression of the NF-κB activating IκB kinase β (IKKβ), but not a kinase inactive mutant, also inhibits HCMV replication. In addition, it was shown that NF-κB signalling is essential for the production of an anti-viral factor in the supernatant of HCMV-infected fibroblasts, and identified interferon-β as this factor. Thus, the role of NF-κB in fibroblasts is to activate a host defence against HCMV.