One of the pressing issues in HIV research is understanding the mechanisms of viral latency, in which small numbers of memory CD4+ T cells harbor a transcriptionally silent form of the integrated provirus. Because this latent virus can be reactivated and because it exists in this dormant form within a long-lived population of lymphocytes, it represents a life-long reservoir. To overcome the in vivo paucity of latently infected memory cells, Williams et al. studied a human T cell line containing a single integrated provirus and found that RNA polymerase II did not bind to the proviral long terminal repeat (LTR) because of alterations in the chromatin structure that had been induced by the binding of the histone deacetylase enzyme HDAC1 to the LTR. Inhibition of HDAC1 or knockdown of NF-κB p50 (which recruits and complexes with HDAC1) were sufficient for the production of short nonproductive viral transcripts, and full viral transcription could be achieved by coexpressing the viral transactivating protein Tat. Establishing this mechanism in primary CD4+ T cells will be the next step in determining whether combinations of HDAC1 inhibition and Tat activation will prove viable as a means of overcoming latency in the clinic. — SJS
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