Reactivation of latent HIV by histone deacetylase inhibitors

Abstract

Latent HIV persists in CD4+ T cells in infected patients under antiretroviral therapy (ART). Latency is associated with transcriptional silencing of the integrated provirus and driven, at least in part, by histone deacetylases (HDACs), a family of chromatin associated proteins that regulate histone acetylation and the accessibility of DNA to transcription factors. Remarkably, inhibition of HDACs is sufficient to reactivate a fraction of latent HIV in a variety of experimental systems. This basic observation led to the shock and kill idea that forcing the transcriptional activation of HIV might lead to virus expression, to virus-or host-induced cell death of the reactivated cells, and to the eradication of the pool of latently infected cells. Such intervention might possibly lead to a cure for HIV infected patients. Here, we review the basic biology of HDACs and their inhibitors, the role of HDACs in HIV latency and recent efforts to use HDAC inhibitors to reactivate latent HIV in vitro and in vivo.

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…Collectively called latencyreversing agents (LRAs), these drugs include histone deacetylase inhibitors (12)(13)(14), PKC activators (15)(16)(17)(18), and the bromodomain inhibitor JQ1 (19)(20)(21). Although LRAs are the subject of intense research, it is unclear how much the LR must be reduced to enable patients to safely discontinue ART.…”

Post-treatment control of HIV infection

“…(ix) Even if PTC is not achievable, a diminished latent reservoir can delay viral rebound upon cessation of treatment. (x) Strategies aimed at reducing the latent reservoir size, either through ART initiated early during primary infection (1,27) or through the use of latency-reversing agents, such as histone deacetylase inhibitors (68,69), DNA methylase inhibitors (70), disulfiram (71), auranofin (30), and activators of protein kinase C or toll-like receptors (72) may enhance the odds that patients attain post-treatment control of HIV infection (SI Appendix, Fig. S5).…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…Provirus refers to the viral form that has been integrated into the cell's genome and is inherited through each cell division. Latent means it is transcriptionally inactive, but is able to re-activate after stimulation [16][17][18][19] and is capable of causing substantial viremia when therapy ceases [20,21] . The viral reservoir, a term used to refer to the latently infected cells as a whole, is maintained throughout the life span of an infected individual.…”