Abstract
A reservoir of latently infected memory CD4(+) T cells is believed to be the source of HIV-1 reemergence after discontinuation of antiretroviral therapy. HIV-1 eradication may depend on depletion of this reservoir. Integrated HIV-1 is inaccessible for expression, in part because of histone deacetylases (HDACs). One approach is to exploit the ability of HDAC inhibitors to induce HIV-1 expression from an integrated virus. With effective antiretroviral therapy, newly expressed HIV-1 is incapable of reinfecting naive cells. With HIV-1 expression, one assumes the infected cell dies and there is a progressive reduction in the size of the reservoir. The concept was tested using the HDAC inhibitor valproic acid. However, valproic acid is weak in inducing HIV-1 from latency in vitro. As such, clinical trials revealed a small or no effect on reducing the number of latently infected T cells in the peripheral blood. However, the new HDAC inhibitors vorinostat, belinostat and givinostat are more effective at targeting specific HDACs for HIV-1 expression than valproic acid. Here, we review studies on HDAC inhibitor-induced expression of latent HIV-1, with an emphasis on new and specific HDAC inhibitors. With increased potency for HIV-1 expression as well as safety and ease of oral administration, new HDAC inhibitors offer a unique opportunity to deplete the latent reservoir. An additional benefit is the antiinflammatory properties of HDAC inhibitors, including downregulation of HIV-1 coreceptor expression.
Highlights
The source of latent HIV-1 infection is a long-lived pool, most likely the latently infected memory T-cell reservoir, harboring integrated HIV-1 proviral DNA [1,2,3,4]
The antiinflammatory and immunosuppressive effect of some histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA; generic vorinostat) and ITF2357 [22], is in part owing to enhancing the production and suppressive function of Tregs by promoting FOXP3 acetylation [23]
A recent study by the Margolis group demonstrated that HDAC inhibitors, which targeted class I HDACs, induced HIV-1 gene expression from cell lines as well as in resting CD4+ T cells of aviremic patients [48]
Summary
TPX, trapoxin; TSA, trichostatin A; RCT, resting CD4+ T cells of aviremic HIV-infected donors; IHI, investigational HDAC inhibitors. The HIV-1 5′ long terminal repeat (LTR), containing the promoter and enhancer elements, has binding sites for several transcription factors and is arranged in two nucleosomes (nuc-0 and nuc-1) [24]. These nucleosomes are positioned in precise locations with respect to different regulatory ele-. In vitro studies revealed that after activation by different stimuli, histone acetyltransferases are recruited to the promoter region, leading to acetylation of both H3 and H4 histones This nuc-1 disruption eventually allows viral transcriptional activation to occur [25,32,33]
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