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S. Prösch, R. Wuttke, D. H. Krüger, H.-D. Volk
NF-?B A Potential Therapeutic Target for Inhibition of Human Cytomegalovirus (Re)activation?
From clinical studies the proinflammatory cytokine TNF? was proposed to play a key role in human cytomegalovirus (HCMV) reactivation from latency. In vitro experiments confirmed that TNF? stimulates the activity of the HCMV IE1/2 enhancer/promoter, which controls immediate early protein IE1 and IE2 gene expression via activation of the transcription factor NF?B and its binding to putative binding sites in the IE1/2 enhancer. NF?B was also proposed to be involved in IE1-mediated autostimulation of this promoter. The IE1/2 enhancer of HCMV contains four putative NF?B binding sites which differ in their distance to the transcription start site as well as in their sequence. Construction and testing of a series of promoter mutants demonstrated that NF?B is essential for both TNF? and IE1 stimulation. Furthermore, we were able to show that although all four NF?B sites bind NF?B with similar affinity in vitro, the contribution to TNF? and IE1 stimulation differs in correlation with the distance to the transcription start site and the sequence. Site 1 and 3 play the most dominant role and site 2 an intermediate, while site 4, which is conserved in sequence but far distant from the transcription start site, had no influence on NF?Bmediated regulation of the IE1/2 promoter. Specific inhibition of NF?B signalling by coexpression of a dominantnegative I?B variant reduced TNF? stimulation of the IE1/2 enhancer/promoter by up to 80%. From this data, inhibitors of NF?B activation are suggested to be an alternative therapeutical strategy to interfere with HCMV (re)activation in undifferentiated monocyte/granulocyte progenitor cells in patients with a high risk of inflammationrelated HCMV (re)activation.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 383, 10/2002
Pages: 1601 - 1609