Targeted Derepression of the Human Immunodeficiency Virus Type 1 Long Terminal Repeat by Pyrrole-Imidazole Polyamides

Abstract

The host factor LSF represses the human immunodeficiency virus type 1 long terminal repeat (LTR) by mediating recruitment of histone deacetylase. We show that pyrrole-imidazole polyamides targeted to the LTR can specifically block LSF binding both in vitro and within cells via direct access to chromatin, resulting in increased LTR expression.

c-Myc and Sp1 Contribute to Proviral Latency by Recruiting Histone Deacetylase 1 to the Human Immunodeficiency Virus Type 1 Promoter

“…Several mechanisms, which are not mutually exclusive, have been proposed to drive HIV-1 proviral quiescence or latency (14,21,37). As the HIV-1 provirus is often integrated into active regions of the host genome, the chromatin environment and the interaction of cellular and viral transcriptional regulators are likely to be critical for inducing and maintaining HIV-1 latency (5,27,37,44). A surprisingly robust induction of HIV-1 transcription in response to deacetylase inhibitors has been observed (19,22,49).…”

Cell Cycle Arrest in G 2 Induces Human Immunodeficiency Virus Type 1 Transcriptional Activation through Histone Acetylation and Recruitment of CBP, NF-κB, and c-Jun to the Long Terminal Repeat Promoter

“…Importantly nuc-1 is also modified during viral activation induced by histone deacetylase inhibitors (34), suggesting a direct link between histone acetylation, nuc-1 conformation, and HIV-1 expression. In that respect, the recruitment of histone deacetylase 1 (HDAC-1) to nuc-1 by YY1 and LSF contributes to the repression of the LTR (6). This interaction is counterregulated by histone deacetylase inhibitors as well as by Tat (16), which has been shown to recruit histone acetyltransferases such as (i) p300 and its homologous cyclic AMP-responsive binding protein (CREB) binding protein (CBP); (ii) p300/CBP-associated factor (pCAF); and (iii) the general control nonderepressible 5 (GCN5) protein to the LTR (3,18).…”

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

“…Approaches, therefore, need to be developed which result in viral transcription without widespread T cell activation. Pyrrole imidazole polyamides are small molecule drugs that can recognise specific HIV sequences [177] and targeting of these small molecules to sequences in the HIV promoter has been shown to block histone deacetylase (HDAC) recruitment, resulting in increased HIV-LTR expression [178]. Viable virus was recovered from pyrrole imidazole polyamide-treated cell cultures of resting CD4+ T-cells, that were originally isolated from aviremic patients on HAART [179].…”