Isoform-Selective Versus Nonselective Histone Deacetylase Inhibitors in HIV Latency Reversal

Abstract

HIV remains incurable due to the persistence of a latent viral reservoir found in HIV-infected cells, primarily resting memory CD4⁺ T cells. Depletion of this reservoir may be the only way to end this deadly epidemic. In latency, the integrated proviral DNA of HIV is transcriptionally silenced partly due to the activity of histone deacetylases (HDACs). One strategy proposed to overcome this challenge is the use of HDAC inhibitors (HDACis) as latency reversal agents to induce viral expression (shock) under the cover of antiretroviral therapy. It is hoped that this will lead to elimination of the reservoir by immunologic and viral cytopathic (kill). However, there are 18 isoforms of HDACs leading to varying selectivity for HDACis. In this study, we review HDACis with emphasis on their selectivity for HIV latency reversal.

Keywords: HDAC inhibitors; HIV; latency reversal; shock and kill; viral reservoir.

FIG. 1.

Chromatin organization of HIV LTR (promoter) and its association with HDACs and transcription factors in the setting of HIV latency. The HIV promoter is arranged in two nucleosomes (nuc 0 and nuc 1) consisting of two copies each of the core histones H2A (black), H2B (blue), H3 (orange), and H4 (green). The nucleotide +1 denotes transcriptional start site on the viral promoter. Transcription factors like RBF2, p50, CTIP2, Sp1, YY1, AP-4, and LSF recruit HDACs to the HIV LTR. These HDACs, in part, promote HIV latency by deacetylating the local histones directly at the provirus integrated site, which in turn brings about repression of chromatin and prevention of RNA polymerase II from binding. HDAC inhibitors block these HDACs and induce histone acetylation, which leads to reactivation of the HIV LTR. AP-4, activating enhancer binding protein; CTIP2, COUP-TF interacting protein; HDACs, histone deacetylases; LSF, late SV40 factor; LTR, long terminal repeats; RBF2, retinoblastoma-family protein 2; YY1, Ying Yang 1.

FIG. 2.

Basic chemical structures of some representative HDAC inhibitors from different families.