Abstract |
Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4(+) T cells is a significant contributor to the persistence of infection, allowing the virus to evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase ( HDAC) inhibitors are capable of inducing expression of quiescent HIV-1 in latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine the specific HDACs that regulate HIV-1 transcription, we evaluated HDAC1 to HDAC11 RNA expression and protein expression and compartmentalization in the resting CD4(+) T cells of HIV-1-positive, aviremic patients. HDAC1, -3, and -7 had the highest mRNA expression levels in these cells. Although all HDACs were detected in resting CD4(+) T cells by Western blot analysis, HDAC5, -8, and -11 were primarily sequestered in the cytoplasm. Using chromatin immunoprecipitation assays, we detected HDAC1, -2, and -3 at the HIV-1 promoter in Jurkat J89GFP cells. Targeted inhibition of HDACs by small interfering RNA demonstrated that HDAC2 and HDAC3 contribute to repression of HIV-1 long terminal repeat expression in the HeLa P4/R5 cell line model of latency. Together, these results suggest that HDAC inhibitors specific for a limited number of class I HDACs may offer a targeted approach to the disruption of persistent HIV-1 infection.
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Authors | Kara S Keedy, Nancie M Archin, Adam T Gates, Amy Espeseth, Daria J Hazuda, David M Margolis |
Journal | Journal of virology
(J Virol)
Vol. 83
Issue 10
Pg. 4749-56
(May 2009)
ISSN: 1098-5514 [Electronic] United States |
PMID | 19279091
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Messenger
- Histone Deacetylases
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Topics |
- CD4-Positive T-Lymphocytes
(metabolism, virology)
- Cytoplasm
(metabolism, virology)
- Gene Expression Regulation, Viral
- HIV Infections
(virology)
- HIV Long Terminal Repeat
- HIV-1
(genetics, physiology)
- HeLa Cells
- Histone Deacetylases
(metabolism)
- Humans
- Jurkat Cells
- Promoter Regions, Genetic
- RNA, Messenger
(metabolism)
- Transcription, Genetic
- Virus Latency
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