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NF-B activation can mediate inhibition of human cytomegalovirus replication

Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 Munich, Germany

Correspondence
Matt Cotten
matt.cotten{at}axxima.com

The activation of NF-B 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-B, and several HCMV gene products have been demonstrated to activate this transcription factor. However, the role of NF-B 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-B for HCMV replication in fibroblasts is presented here. Using both genetic and pharmaceutical methods, it was shown that blocking NF-B 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- and interferon-, no longer inhibit HCMV when NF-B activation is blocked. Furthermore, forced expression of the NF-B activating IB kinase (IKK), but not a kinase inactive mutant, also inhibits HCMV replication. In addition, it was shown that NF-B signalling is essential for the production of an anti-viral factor in the supernatant of HCMV-infected fibroblasts, and identified interferon- as this factor. Thus, the role of NF-B in fibroblasts is to activate a host defence against HCMV.

Supplementary material available in JGV Online.

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