Factors Controlling Chromatin Organization and Nucleosome Positioning for Establishment and Maintenance of HIV Latency

Abstract

Transcription of the integrated HIV provirus is subject to regulation by chromatin organization and must employ host cell transcription factors and chromatin modifying complexes to promote the formation of latency, and then reverse this process to replicate in response to T cell activation. The repressed latent HIV-1 proviral 5' LTR is organized into a defined structure where two de-acetylated and positioned nucleosomes flank the enhancer region, presumably imposing a block to transcriptional initiation and elongation. LTR-associated nucleosomes undergo further histone H3 K9 trimethylation, to cause silencing by recruitment of HP1. In this article, we review current understanding of how the transcriptionally silenced provirus might be established through the function of transcription factors that bind conserved cis-elements, including SP1, YY1, NF-kappaB, CBF-1 and RBF-2 (USF/TFII-I), and propose mechanisms by which factors bound to the repressed LTR can enable reactivation in response to cell signaling.

The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

“…Histone acetylation is a marker of active chromatin and is increased on the activated HIV LTR [8,9] (Fig. 2B).…”

“…A variety of strategies have been considered to force expression of latent HIV with the objective of ''purging'' this otherwise impenetrable infection [3], which include the use of histone deacetylase (HDAC) inhibitors to cause remodeling of nucleosomes at the LTR and force increased expression [4][5][6][7]. This approach shows some promise [6,7], but because latent HIV genomes are silenced by mechanisms associated with heterochromatin [8,9], it is unlikely that HDAC inhibitors alone will be capable of purging the entire population of latently infected cells.…”

Sequence Insertions in the HIV Type 1 Subtype C Viral Promoter Predominantly Generate an Additional NF-κB Binding Site

“…7 In the context of subtype B, the RBEIII site binds a transcription factor complex RBF-2 that largely functions as a strong transcription repressor. 8 Interestingly, some of the new subtype C viral strains contain two genetically intact RBEIII sites (02-9, Seva9, and EF592602, Fig. 1) unlike in subtype B where RBEIII duplication was demonstrated only as a compensatory mechanism for the loss of the original site.…”

“…In subtype B, the RBEIII site binds a transcription factor complex of variable composition, RBF-2, that functions as a strong transcription repressor. 8 Of note, the MFNLP insertions in the subtype B LTR (B-LTR) are strictly restricted to duplicating the RBEIII site only as a compensatory mechanism when the original site is inactivated by the natural variation. 9 Importantly, MFNLP sequence insertions in subtype C LTR have not been reported previously, although a few sequences deposited to the databases contained such elements.…”

Progress and challenges in the use of latent HIV-1 reactivating agents

“…Two nucleosomes (nuc-0 and nuc-1) that assemble around transcription sites harbor markers of silent heterochromatin, such as low acetylation of histones, lysine 9 trimethylated histone 3 (H3K9me3) and heterochromatin protein 1 (HP1) [31] . Disruption of nucleosomes by acetylation upon recruitment of histone acetyltransferase allows viral transcriptional activation to occur.…”