CTD kinases are critical for the elongation of HIV transcription and co-transcriptional processing of viral transcripts. They function after chromatin remodeling and before translation of viral proteins. Thus, our project will interface well with those of Greene, Ott and Verdin on epigenetic regulation ofthe integrated provirus. Manipulations that change the HIV epigenome will then be evaluated with respect to their effects on CTD kinases, for which we not only have the reagents but also a greater understanding of their function. It is more than likely that high throughput screens in these other projects will identify compounds that will affect P-TEFb, CycK or CycL complexes, or that will act in concert with agonists that affect primarily these CTD kinases'. In addition, studies by Karn on effects of cellular signaling on P-TEFb and NF-kB will allow us to his latency model to test our ideas on CycK and CycL complexes as well. It is also possible that effects of Nef are not mediated via P-TEFb but rather disregulate subunits of CycK, By differentially affecting HIV splicing and polyadenylation, they might allow more cells to enter proviral latency.

Public Health Relevance

The projects in mouse and macaque models in the HIV Collaboratory will directly contribute to several Important objectives ofthe Collaboratory including identification of the range of cells and tissues harboring latent proviruses, dissection of molecular mechanisms underlying HIV latency, and discovery and evaluation of new compounds and strategies for successfully purging the virus from the latent reservoirs or establishing a drug-free remission.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of North Carolina Chapel Hill
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