|Knowles, Donald - Don|
Submitted to: Virology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/11/2006
Publication Date: 8/15/2006
Citation: Murphy, B.G., Hotzel, I., Jasmer, D.P., Davis, W.C., Knowles Jr, D.P. 2006. TNFalpha and GM-CSF-induced activation of the CAEV promoter is independent of AP-1. Virology. 352(1):188-199. Interpretive Summary: Lentiviruses of small ruminants which include caprine arthritis-encephalitis virus of goats and ovine progressive pneumonia virus of sheep continue to cause economic losses due to their ability to cause long-term inflammation. This work was directed at determining how these viruses interact with their hosts (goats and sheep) to initiate and or maintain the inflammation. This work showed that an a modulator of inflammation, tissue necrosis factor alpha (TNF-alpha) increases the expression of virus. The intended long-term objective is to learn how virus is maintained in the hosts and through this knowledge discover methods to block virus replication and/or pathways to inflammation.
Technical Abstract: Caprine arthritis encephalitis virus transcription is under the control of the viral promoter within the long terminal repeat. Previous studies with the closely related maedi visna lentivirus have indicated that viral transcription is dependent upon the AP-1 transcription factor. Other studies have indicated a potential role for the cytokines TNF' and GM-CSF in CAEV pathogenesis by increasing viral loads in infected tissues. The hypotheses that AP-1 transcription factors are necessary for transcriptional activation of the CAEV promoter and that CAEV transcriptional activation results from treatment with the cytokines GM-CSF and TNF' were tested with a stably transduced U937 cell line. Here we found that TNF' and GM-CSF activated CAEV transcription in U937 cells. However, this activation effect was not blocked by SP600125, an inhibitor of Jun N-terminal kinase. SP600125 effectively prevented Jun phosphorylation in cells subsequently treated with cytokines. The cytokines TNF' and GM-CSF therefore activate CAEV transcription, and this effect occurs independently of AP-1. A set of progressive deletion mutants was utilized to determine that TNF'-induced expression is dependent upon an element or elements within the U3 70 bp repeat.