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The effect of transcription factor YY1 and small molecules on HIV-1 expression

University of British Columbia

Current therapies to treat patients infected with HIV-1 do not represent a cure. The virus persists as a latent chromosomally integrated provirus in unstimulated helper T-cells that is unaffected by current drugs and can become reactivated upon stimulation of the T-cell receptor. Much research is currently focused on understanding mechanisms that control HIV-1 latency and devising ways to eliminate latent viral populations. In this thesis, I characterize a protein, YY1 that is involved in establishing HIV-1 latency, examine the role of a histone methyltransferase inhibitor on activation of the HIV-1 LTR, and identify lariat peptides that recognize TFII-I to examine the role of an interaction between USF1 and TFII-I on HIV-1 transcription. The transcription factor YY1 has been shown to promote repressive chromatin modifications by the recruitment of histone deacetylases (HDACs). In this thesis, I identify a novel binding site for YY1 on the HIV-1 LTR, near the highly conserved RBEIII element immediately upstream of the enhancer, and show that YY1 dissociates from the LTR in vivo upon T-cell activation. Overexpression of YY1 causes an increase in HIV-1 expression, which illustrates the importance of this factor for establishment of latency. I also show that an inhibitor of the histone methlytransferase SUV39H1, chaetocin, causes induction of latent HIV-1 expression, with minimal cell toxicity and without T-cell activation. The effect of chaetocin is amplified synergistically in combination with histone deacetylase (HDAC) inhibitors. These results indicate that drugs with properties similar to chaetocin may provide a therapy to purge cells of latent HIV-1, possibly in combination with other chromatin remodeling drugs. In a parallel objective, I sought to identify cyclic lariat peptide inhibitors of TFII-I, an additional factor shown to be involved in expression of HIV-1 transcription. In these studies, I identified a lariat peptide that binds the R4 domain of TFII-I using a yeast two-hybrid assay. Expression of this peptide in cells was found to activate the HIV-1 LTR 2-fold. This result demonstrates that lariat peptide inhibitors might offer an alternative to small molecule compounds as potential therapies targeting the latent reservoir.

Text

2014-04-29

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/46610

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/