Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors.
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.
Ylisastigui
Loyda
L
University of Texas Southwestern Medical Center at Dallas, Department of Medicine, Division of Infectious Diseases, Dallas, Texas 75390-9113, USA.
Coull
Jason J
JJ
Rucker
Victor C
VC
Melander
Christian
C
Bosch
Ronald J
RJ
Brodie
Scott J
SJ
Corey
Lawrence
L
Sodora
Donald L
DL
Dervan
Peter B
PB
Margolis
David M
DM
D019380:Anti-HIV Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000821:virology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000302:isolation & purification; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009757:Nylons / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D017735:Virus Latency / Q000187:drug effects*
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D016655:HIV Core Protein p24; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012367:RNA, Viral; C029899:imidazole; D006655:Histone Deacetylases