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Arya Suresh; Holczbauer, Agnes
JAIDS Journal of Acquired Immune Deficiency Syndromes: January 2016
doi: 10.1097/01.qai.0000479707.55951.8e
Abstract: PDF Only

The idea that it may be possible to “cure” AIDS is beginning to be accepted. Whether that is realistic or a pipe dream remains to be seen. The impediment is HIV latency. Thinking is that (1) if we could wake up the virus and (2) kill it without allowing it to infect naive cells, the battle would be won. To our knowledge no sure-fire way of doing either currently exists. Not surprising, different drugs activate silent virus differentially in cell cultures or in patients. HIV latency essentially is transcriptional block—resulting from block of transcriptional initiation due to limiting transcriptional factors (eg, NFkB); suppression of transcriptional elongation due insufficiency of Tat; epigenetic modification of the viral genome by promoter methylation; or chromatin remodeling by histone acetylation. It makes sense then to target multiple blocks by a combinatorial approach. We have tested this idea in a cell culture model of latency where provirus carries reporter GFP gene and its activation is scored by GFP flow cytometry. We have used (1) prostratin to activate NFkB, (2) Tat to promote transcript elongation, (3) Aza CdR to demethylate the viral promoter, and (4) HDAC inhibitor SAHA to uncondense the chromatin. The results confirm that combination of agents is more effective than single agents. For example, prostratin alone and prostratin plus Tat increased GFP expression by 20 and 100 folds, respectively. Tat alone only minimally activated. Tat being an elongation factor, unless transcription has been initiated, there is nothing to elongate. This work was supported by the intramural program of NCI (2011–2012). The opinions expressed here are those of the authors and not of the National Cancer Institute.

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