Polyamides Reveal a Role for Repression in Latency within Resting T Cells of HIV‐Infected Donors

Abstract

We identify histone deacetylation as a mechanism that can dampen viral expression in infected, activated CD4+ T cells and establish a persistent, quiescent reservoir of HIV infection.

Human Immunodeficiency Virus Type 1 Can Establish Latent Infection in Resting CD4+T Cells in the Absence of Activating Stimuli

“…Using our model we can ask questions that are difficult to study in vivo due to the low level of latently infected cells (24,35,42,43,50,75 ϩ T-cell subsets (11,53)? In summary, our in vitro system provides a new model of HIV-1 latency that can be used to answer questions about HIV-1 latency and, ultimately, to test therapies aimed at diminishing HIV-1 reservoirs.…”

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

“…Histone modifications remodel the chromatin of the viral promoter region but also regulate the functional properties of cellular and viral transcription factor binding to the HIV-1 long terminal repeat (LTR) (28,40,45,50). By altering histones, recruiting other chromatin-remodeling factors, and altering the activity of transcription factors, histone deacetylases (HDACs) appear to be critical for the repression of HIV-1 transcription and the maintenance of HIV-1 latency (45,50).…”

“…By altering histones, recruiting other chromatin-remodeling factors, and altering the activity of transcription factors, histone deacetylases (HDACs) appear to be critical for the repression of HIV-1 transcription and the maintenance of HIV-1 latency (45,50). In support of the clinical relevance of this model, we found that the administration of an HDAC inhibitor, valproic acid (VPA), in the context of intensified highly active antiretroviral therapy depleted latent HIV-1 infection in vivo (23), although this was not observed in a clinical cohort on standard antiretroviral therapy and incidentally coadministered VPA (41).…”

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

“…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]. HDAC inhibitors have also been shown to release integrated HIV from latency in the HIV reservoir [180].…”