Transcriptional repression of human immunodeficiency virus type 1 by AP-4.
Elucidation of the mechanism of transcriptional silencing of human immunodeficiency virus type 1 (HIV-1) provirus in latently infected cells is crucial to understand the pathophysiology of HIV-1 infection and to develop novel therapies. Here we demonstrate that AP-4 is responsible for the transcriptional repression of HIV-1. We found that AP-4 site within the viral long terminal repeat (LTR) is well conserved in the majority of HIV-1 subtypes and that AP-4 represses HIV-1 gene expression by recruiting histone deacetylase (HDAC) 1 as well as by masking TATA-binding protein to TATA box. AP-4-mediated transcriptional repression was inhibited by an HDAC inhibitor, tricostatin A, and could be exerted even at distant locations from the TATA box. In addition, AP-4 interacted with HDAC1 both in vivo and in vitro. Moreover, chromatin immunoprecipitation assays have revealed that AP-4 and HDAC1 are present in the HIV-1 LTR promoter in latently infected ACH2 and U1 cells, and they are dissociated from the promoter concomitantly with the association of acetylated histone H3, TBP, and RNA polymerase II upon TNF-alpha stimulation of HIV-1 replication. Furthermore, when AP-4 is knocked down by siRNA, HIV-1 production was greatly augmented in cells transfected with a full-length HIV-1 clone. These results suggest that AP-4 may be responsible for transcriptional quiescence of latent HIV-1 provirus and give a molecular basis to the reported efficacy of combination therapy of conventional anti-HIV drugs with an HDAC inhibitor in accelerating the clearance of HIV-1 from individuals infected with the virus.
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan.
Kenichi
K
Imai
Takashi
T
Okamoto
D000998:Antiviral Agents / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D006678:HIV / Q000378:metabolism*; D016655:HIV Core Protein p24 / Q000737:chemistry; D018922:HL-60 Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D020079:Terminal Repeat Sequences; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D000998:Antiviral Agents; D002843:Chromatin; D004268:DNA-Binding Proteins; D016655:HIV Core Protein p24; D006657:Histones; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases