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

Autor: Ylisastigui, Loyda, Coull, Jason J., Rucker, Victor C., Melander, Christian, Bosch, Ronald J., Brodie, Scott J., Corey, Lawrence, Sodora, Donald L., Dervan, Peter B., Margolis, David M.
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Zdroj: Journal of Infectious Diseases; 10/15/2004, Vol. 190 Issue 8, p1429-1437, 9p
Abstrakt: 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 HW-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 HW infection. [ABSTRACT FROM AUTHOR]
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