A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression.
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.
Keedy
Kara S
KS
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 3302 Michael Hooker Research Ctr., CB#7435, Chapel Hill, NC 27599-7435, USA.
Archin
Nancie M
NM
Gates
Adam T
AT
Espeseth
Amy
A
Hazuda
Daria J
DJ
Margolis
David M
DM
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D003593:Cytoplasm / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000821:virology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D017735:Virus Latency
D012333:RNA, Messenger; D006655:Histone Deacetylases