Targeting HIV latency: pharmacologic strategies toward eradication

Abstract

The latent reservoir for HIV-1 in resting CD4(+) T cells remains a major barrier to HIV-1 eradication, even though highly active antiretroviral therapy (HAART) can successfully reduce plasma HIV-1 levels to below the detection limit of clinical assays and reverse disease progression. Proposed eradication strategies involve reactivation of this latent reservoir. Multiple mechanisms are believed to be involved in maintaining HIV-1 latency, mostly through suppression of transcription. These include cytoplasmic sequestration of host transcription factors and epigenetic modifications such as histone deacetylation, histone methylation and DNA methylation. Therefore, strategies targeting these mechanisms have been explored for reactivation of the latent reservoir. In this review, we discuss current pharmacological approaches toward eradication, focusing on small molecule latency-reversing agents, their mechanisms, advantages and limitations.

Conflict of interest statement

Conflicts of interest

The authors have no conflict of interest to declare.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1. The maintenance of HIV-1 latency and reactivation of latent HIV-1 provirus

The HIV-1 DNA is depicted as a green ribbon, with the two nucleosomes, Nuc-0 and Nuc-1, depicted as blue spheres. Parts of the HIV-1 5'LTR that contain binding sites for major transcription factors (boxes in purple, blue and pink) and the transcriptional start site (TSS, yellow triangle) are highlighted in light yellow. (a) The maintenance of HIV-1 latency and potential targets for reactivation. In latent infection, HDACs and HMTs are recruited to HIV-1 LTR, resulting in histone deacetylation and methylation on Nuc-0 and Nuc-1, which leads to a restrictive environment for transcription initiation. DNA methyltransferases could introduce DNA methylation on the CpG islands, which could further silence transcription. Most host transcriptional factors are sequestered in cytoplasm in resting cells. The inactive NF-κB p50 homodimer binds to the NF-κB site at HIV-1 LTR, whereas the active form, a p65/p50 heterodimer, is bound by IκB in the cytoplasm. NFAT is in its phosphorylated inactive form. pTEFb is restricted in a transcriptionally inactive complex with Hexim-1 and 7SK snRNA. To overcome these obstacles to transcription of the HIV-1 provirus agents targeting these restrictive steps have been explored for the reactivation of latent HIV-1 (red arrows). (b) The active transcription of HIV-1 provirus. Upon cellular activation, IκB is phosphorylated and degraded, releasing p65/p50 which translocates into nucleus and binds to NF-κB sites on HIV-1 LTR. HATs are recruited to LTR, and acetylation disrupts histone–DNA binding, facilitating the recruitment of transcription factors and complexes. Cellular activation also results in the release of active pTEFb which phosphorylates the C-terminal domain of RNA polymerase II (RNA Pol II), stimulating transcriptional elongation. After the stem-loop structure of TAR is transcribed, HIV-1 Tat efficiently recruits active pTEFb to TAR, further stimulating the elongation of HIV-1 transcripts.