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J Infect Dis. 2004 Oct 15;190(8):1429-37. Epub 2004 Sep 15.

Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors.

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  • 1University of Texas Southwestern Medical Center at Dallas, Department of Medicine, Division of Infectious Diseases, Dallas, Texas 75390-9113, USA.

Abstract

BACKGROUND:

The persistence of human immunodeficiency virus (HIV) type 1 within resting CD4+ T cells poses a daunting therapeutic challenge. Histone deacetylase (HDAC)-1, a chromatin-remodeling enzyme that can mediate gene silencing, is recruited to the HIV-1 long terminal repeat by the host transcription factor LSF. Pyrrole-imidazole polyamides, small molecules that target specific DNA sequences, can access the nucleus of cells and specifically block transcription-factor binding.

METHODS:

We used polyamides to directly test the role of chromatin remodeling in HIV quiescence in primary resting CD4+ T cells obtained from HIV-infected patients.

RESULTS:

After exposure to any of 4 different polyamides that specifically block HDAC-1 recruitment by LSF to the HIV promoter, replication-competent HIV was recovered from cultures of resting CD4+ T cells in 6 of 8 HIV-infected patients whose viremia had been suppressed by therapy. In comparison, HIV was not recovered after exposure to control, mismatched polyamides but was recovered from 7 of 8 of these patients' samples after the activation of T cells.

CONCLUSIONS:

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.

Copyright 2004 Infectious Diseases Society of America

PMID:
15378435
[PubMed - indexed for MEDLINE]
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