Furuya Andrea Kinga Marias, Sharifi Hamayun J, Jellinger Robert M, Cristofano Paul, Shi Binshan, de Noronha Carlos M C
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
Division of HIV Medicine, Albany Medical Center, Albany, New York, United States of America.
PLoS Pathog. 2016 Apr 19;12(4):e1005581. doi: 10.1371/journal.ppat.1005581. eCollection 2016 Apr.
Marburg virus, the Kaposi's sarcoma-associated herpesvirus (KSHV) and Dengue virus all activate, and benefit from, expression of the transcription regulator nuclear erythroid 2-related factor 2 (Nrf2). The impact of Nrf2 activation on human immunodeficiency virus (HIV) infection has not been tested. Sulforaphane (SFN), produced in cruciferous vegetables after mechanical damage, mobilizes Nrf2 to potently reprogram cellular gene expression. Here we show for the first time that SFN blocks HIV infection in primary macrophages but not in primary T cells. Similarly SFN blocks infection in PMA-differentiated promonocytic cell lines, but not in other cell lines tested. siRNA-mediated depletion of Nrf2 boosted HIV infectivity in primary macrophages and reduced the anti-viral effects of SFN treatment. This supports a model in which anti-viral activity is mediated through Nrf2 after it is mobilized by SFN. We further found that, like the type I interferon-induced cellular anti-viral proteins SAMHD1 and MX2, SFN treatment blocks infection after entry, but before formation of 2-LTR circles. Interestingly however, neither SAMHD1 nor MX2 were upregulated. This shows for the first time that Nrf2 action can potently block HIV infection and highlights a novel way to trigger this inhibition.
马尔堡病毒、卡波西肉瘤相关疱疹病毒（KSHV）和登革热病毒都会激活转录调节因子核红细胞2相关因子2（Nrf2）的表达并从中获益。Nrf2激活对人类免疫缺陷病毒（HIV）感染的影响尚未得到测试。十字花科蔬菜在受到机械损伤后会产生萝卜硫素（SFN），它能促使Nrf2有力地重新编程细胞基因表达。在此，我们首次表明，SFN可阻断原代巨噬细胞中的HIV感染，但不能阻断原代T细胞中的感染。同样，SFN可阻断佛波酯（PMA）分化的原单核细胞系中的感染，但不能阻断其他测试细胞系中的感染。小干扰RNA（siRNA）介导的Nrf2缺失增强了原代巨噬细胞中的HIV感染性，并降低了SFN治疗的抗病毒效果。这支持了一种模型，即抗病毒活性是在SFN动员Nrf2后通过Nrf2介导的。我们进一步发现，与I型干扰素诱导的细胞抗病毒蛋白SAMHD1和MX2一样，SFN治疗在病毒进入后但在2-LTR环形成之前阻断感染。然而，有趣的是，SAMHD1和MX2均未上调。这首次表明Nrf2的作用可有力地阻断HIV感染，并突出了一种引发这种抑制作用的新方法。
