selective histonedeacetylase inhibitor m344 intervenes in hiv-1 latency through increasing histone acetylation and activation of nf-kappab选择性histonedeacetylase抑制剂m344干涉hiv - 1通过增加组蛋白乙酰化作用和激活nf-kappab延迟.pdfVIP

Selective Histonedeacetylase Inhibitor M344 Intervenes in HIV-1 Latency through Increasing Histone Acetylation and Activation of NF-kappaB . . . Hao Ying , Yuhao Zhang , Xin Zhou , Xiying Qu, Pengfei Wang, Sijie Liu, Daru Lu, Huanzhang Zhu* State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China Abstract Background: Histone deacetylase (HDAC) inhibitors present an exciting new approach to activate HIV production from latently infected cells to potentially enhance elimination of these cells and achieve a cure. M344, a novel HDAC inhibitor, shows robust activity in a variety of cancer cells and relatively low toxicity compared to trichostatin A (TSA). However, little is known about the effects and action mechanism of M344 in inducing HIV expression in latently infected cells. Methodology/Principal Findings: Using the Jurkat T cell model of HIV latency, we demonstrate that M344 effectively reactivates HIV-1 gene expression in latently infected cells. Moreover, M344-mediated activation of the latent HIV LTR can be strongly inhibited by a NF-kB inhibitor aspirin. We further show that M344 acts by increasing the acetylation of histone H3 and histone H4 at the nucleosome 1 (nuc-1) site of the HIV-1 long terminal repeat (LTR) and by inducing NF-kB p65 nuclear translocation and direct RelA DNA binding at the nuc-1 region of the HIV-1 LTR. We also found that M344 synergized with prostratin to activate the HIV-1 LTR promoter in latently infected cells. Conclusions/Significance: These results suggest the potential of M344 in anti-latency therapies and an important role for histone modifications and NF-kB transcription factors in regulating HIV-1 LTR gene expression. Citation: Ying H, Zhang Y, Zhou X, Qu