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Published October 15, 2004 | public
Journal Article

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

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. 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.

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.

Additional details

Created:
August 19, 2023
Modified:
October 24, 2023