Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 190, Issue 8, Pages 1429-1437Publisher
OXFORD UNIV PRESS INC
DOI: 10.1086/423822
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Funding
- NIAID NIH HHS [AI 046376, AI 45297] Funding Source: Medline
- NIDCR NIH HHS [DE12926] Funding Source: Medline
- NIGMS NIH HHS [GM51747, GM19789] Funding Source: Medline
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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.
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