Identification of the cellular transcription factor KLF16 as a novel repressive epigenetic repressor of HIV-1 transcription

Abstract

Despite antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1) persists in latently-infected cells through epigenetic and transcriptional mechanisms. Latency-reversing agents have failed clinically, partly due to incomplete understanding of HIV-1 latency reversal. Here, using DNA-affinity capture and mass spectrometry on the HIV-1 5 long terminal repeat (5LTR) enhancer-core promoter, we identify KLF16 (Kruppel-like Factor 16) as a novel regulator of HIV-1 gene expression. KLF16 binds to the HIV-1 5LTR in vivo at Sp1 binding sites, and KLF16 depletion reactivates latent HIV-1 in T-lymphoid and monocytic cell models. Mechanistically, KLF16 represses HIV-1 transcription by competing with Sp1 for promoter binding and by recruiting the Sin3A/HDAC1 and HP1/Suv39H1 repressive epigenetic complexes. KLF16 is also upregulated in CD4+ T cells from ART-treated people with HIV-1 upon T-cell activation. Additionally, All-Trans retinoic acid (ATRA) reactivates latent HIV-1 in myeloid cells, partly by downregulating KLF16. These findings establish KLF16 as a novel transcriptional repressor of HIV-1, identifying it as a potential promising therapeutic target for cure strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/722432v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1611026org.highwire.dtl.DTLVardef@16b5eaforg.highwire.dtl.DTLVardef@153b11org.highwire.dtl.DTLVardef@1d90330_HPS_FORMAT_FIGEXP M_FIG C_FIG