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

Ylisastigui, Loyda and Coull, Jason J. and Rucker, Victor C. and Melander, Christian and Bosch, Ronald J. and Brodie, Scott J. and Corey, Lawrence and Sodora, Donald L. and Dervan, Peter B. and Margolis, David M. (2004) Polyamides Reveal a Role for Repression in Latency within Resting T Cells of HIV-Infected Donors. Journal of Infectious Diseases, 190 (8). pp. 1429-1437. ISSN 0022-1899. doi:10.1086/423822.

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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. Pyrroleimidazole 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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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2004 Infectious Diseases Society of America. Received 21 February 2004; accepted 30 March 2004; electronically published 15 September 2004. Presented in part: 5th International Workshop on HIV Drug Resistance and Treatment Strategies, Scottsdale, Arizona, 4–8 June 2001 (abstract 34); Keystone Symposium, Twenty Years of HIV Research: From Discovery to Understanding, Banff, Alberta, Canada, 29 March–4 April 2003 (abstract 148). Financial support: National Institutes of Health (postdoctoral grant GM19789 to C.M. and grants AI 45297 and AI 046376 to D.M.M., DE12926 to D.L.S., and GM51747 to P.B.D.). Potential conflicts of interest: P.B.D. has declared a financial interest in a company whose potential product was studied in the present work. We thank Ginger Lehrman, Aneta Wozniakowski, Kurt Diem, and Holly Johnson for excellent technical assistance; Holly Wise, for study coordination; Mary Beth Kvanli and Diana Turner, for patient care; B. Yazdani, for subject referral; Lindsey Inman and the Dallas Veterans Affairs Medical Center, for support of translational clinical research; Christopher Gilpin and the University of Texas Southwestern Molecular and Cellular Imaging Facility, for confocal microscopy; the staff of the Carter BloodCare Center, for their assistance with leukopheresis; and J. Victor Garcia and Robert Munford, for advice and review of the manuscript.
Funding AgencyGrant Number
NIH Postdoctoral FellowshipGM-19789
Issue or Number:8
Record Number:CaltechAUTHORS:20111019-095242663
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Official Citation:Loyda Ylisastigui, Jason J. Coull, Victor C. Rucker, Christian Melander, Ronald J. Bosch, Scott J. Brodie, Lawrence Corey, Donald L. Sodora, Peter B. Dervan, and David M. Margolis Polyamides Reveal a Role for Repression in Latency within Resting T Cells of HIV-Infected Donors J Infect Dis. (2004) 190 (8): 1429-1437 doi:10.1086/423822
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27302
Deposited On:19 Oct 2011 18:42
Last Modified:09 Nov 2021 16:47

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