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.

Figure 1. Classification of HDAC isotypes

18 HDACs have been identified in mammalian cells, and classified into four groups based on sequence similarity of the catalytic domain to yeast prototypes. Class I HDACs include the yeast RPD3 homologues, HDAC1, 2, 3, 8. Class II HDACs include the yeast HDA1/2 homologues, HDAC4, 5, 6, 7, 9, 10, and are further subclassified as IIa (HDAC4, 5, 7, 9) and IIb (HDAC6, 10). Class III HDACs (also known as sirtuins) include the yeast Sir2 orthologues, SIRT1, 2, 3, 4, 5, 6, 7. Class IV HDACs include HDAC11, which has sequence similarity to both RPD3 and HDA1. N, M and C in localization indicate nuculear, mitochondrial and cytoplasmic, respectively. Sizes are in kDa.

Figure 2. Basic structure of HDAC inhibitors

HDAC inhibitors possess a cap group for HDAC surface recognition, a linker (aliphatic chain) and a functional group (highlighted in red) that chelates the zinc cation in the active enzymatic center. The thiol group of romidepsin serves as functional group after it becomes reduced in the intracellular environment. Known HDAC targets of the HDAC inhibitors are listed after each compound.

Figure 3. Mechanisms for reactivation of latent HIV by HDAC inhibitors

(A) Transcription factors such as RBF2, NF-κB p50, CBF1, Sp1 and YY1 recruit HDACs to the HIV LTR. The BAF complex, which is necessary for the position of the repressor nucleosome nuc-1 at the HIV transcriptional start site, also contains HDAC1 and 2. MBD2 recognizes methylated DNA downstream of nuc-1 and recruits the NuRD complex, which also contains HDAC1 and HDAC2. HDAC inhibitors block these HDACs and directly induce histone acetylation, which leads to the reactivation of the HIV LTR promoter. (B) Full activation of NF-κB (p65–p50) is negatively regulated by HDAC3 through deacetylation. HDAC3 inhibition induces the hyperactivation of the NF-κB factor and to latent HIV reactivation. Sp1 is negatively regulated by HDAC1. HIV Tat is also regulated by acetylation. (C) HDAC inhibitors may also activate the expression of a gene whose product positively regulates HIV transcription.