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Review
. 2011 May-Jun;17(5-6):466-72.
doi: 10.2119/molmed.2011.00076. Epub 2011 Mar 15.

Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir

Shay Matalon  1 , Thomas A Rasmussen, Charles A Dinarello
Affiliations
Review

Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir

Shay Matalon et al. Mol Med. 2011 May-Jun.

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.

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Figures

Figure 1
Figure 1
HDAC suppression of HIV-1 expression in latent CD4+ T cells. (A) In the latent state, HDAC-1, −2 and −3 are recruited to the proviral LTR by different DNA binding proteins. Lysine residues on histones on nuc-1 are hypoacetylated and viral transcription is blocked. (B) Upon activation of the cell by exogenous stimuli, HDACs are replaced by his-tone acetyltransferases and nuc-1 is hyperacetylated with chromatin remodeling and viral gene transcription. Adapted from Colin and Van Lint (64).
Figure 2
Figure 2
HIV-1 expression in U1 cells stimulated by ITF2357, PXD101, SAHA or VPA. Mean ± SEM p24 levels of two separate experiments for HDAC inhibitors (HDACi) are indicated under the horizontal axis. Phorbol-12-myristate-13-acetate (PMA) is used as the positive control (omitted from figure). ITF2357 was supplied by Italfar-maco, SpA, Cinisello Balsamo, Italy; PXD101 and SAHA were purchased through Selleck Chemicals LLC (Houston, TX, USA).
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