Short communication: activation of latent HIV type 1 gene expression by suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor approved for use to treat cutaneous T cell lymphoma.
The ability of HIV to establish a latent infection causes life-long virus persistence, even after long-term highly active antiretroviral therapy (HAART). The role that latency is playing in preventing clearance of the virus infection has become evident in recent years. Patients who have been successfully treated with ART, having undetectable levels of viral RNA (below 50 copies/ml) in the plasma for years, experienced rapid virus rebound on withdrawal of therapy. Activation of latent proviruses from the infected cells in combination with ART is a therapeutic strategy that may lead to the complete elimination of HIV infection. We report here that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor that has been approved for the treatment of cutaneous T cell lymphoma (CTCL), can activate an HIV-1 vector provirus in a cell model system. Treatment of cells harboring a latent, HIV-1-derived provirus caused activation of both early and late viral gene expression, acetylation of nucleosome on the 5' long terminal repeat (LTR), and remodeling of the chromatin at the 5' LTR. Several compounds, including valproic acid, have been tested for their ability to activate latent HIV-1, but have met with disappointing results. SAHA, a relatively nontoxic, FDA-approved compound, should be considered for developing a strategy to eliminate HIV from patients.
Edelstein
Leonard C
LC
Department of Molecular Genetics, Microbiology and Immunology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Micheva-Viteva
Sophia
S
Phelan
Bradley D
BD
Dougherty
Joseph P
JP
D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008214:Lymphocytes / Q000821:virology*; D011533:Proviruses / Q000187:drug effects; D014775:Virus Activation; D017735:Virus Latency / Q000187:drug effects*; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat
Mol Cell Biol. 2002 May;22(9):2965-73
11940654
J Biol Chem. 2009 Mar 13;284(11):6782-9
19136668
J Biol Chem. 2006 May 5;281(18):12495-505
16540471
Oncologist. 2007 Oct;12(10):1247-52
17962618
J Virol. 2000 Aug;74(15):6790-9
10888618
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3921-6
15001702
Nat Biotechnol. 2007 Jan;25(1):84-90
17211407
Nat Med. 2000 Jul;6(7):757-61
10888923
J Immunol. 2001 Oct 15;167(8):4494-503
11591776
EMBO J. 2006 Jan 11;25(1):139-49
16319923
J Neurovirol. 2006 Oct;12(5):403-6
17065134
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2995-3000
11867742
Antimicrob Agents Chemother. 2005 Dec;49(12):5185-8
16304201
Nat Struct Mol Biol. 2007 Nov;14(11):1008-16
17984963
Oncogene. 2007 Feb 26;26(9):1351-6
17322921
Lancet. 2005 Aug 13-19;366(9485):549-55
16099290
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15109-14
10611346
Mol Cell Biol. 2003 Apr;23(8):2749-61
12665576
J Infect Dis. 2007 Mar 15;195(6):833-6
17299713
J Virol. 2007 Oct;81(20):10914-23
17670825
Mol Cell Biol. 1998 May;18(5):2535-44
9566873
AIDS. 2004 May 21;18(8):1101-8
15166525
Nat Med. 1999 May;5(5):512-7
10229227
EMBO J. 1993 Aug;12(8):3249-59
8344262
J Biol Chem. 2005 Mar 25;280(12):11192-202
15671023
EMBO J. 1996 Mar 1;15(5):1112-20
8605881
EMBO J. 2007 Dec 12;26(24):4985-95
18007589