Faith Seth A, Sweet Thomas J, Bailey Erin, Booth Tristan, Docherty John J
Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
Antiviral Res. 2006 Dec;72(3):242-51. doi: 10.1016/j.antiviral.2006.06.011. Epub 2006 Jul 14.
Resveratrol inhibits herpes simplex virus (HSV) replication by an unknown mechanism. Previously it was suggested that this inhibition may be mediated through a cellular factor essential for HSV replication [Docherty, J.J., Fu, M.M., Stiffler, B.S., Limperos, R.J., Pokabla, C.M., DeLucia, A.L., 1999. Resveratrol inhibition of herpes simplex virus replication. Antivir. Res. 43, 145-155]. After examining numerous cellular factors, we report that resveratrol suppresses NF-kappaB (NF-kappaB) activation in HSV infected cells. Reports have indicated that HSV activates NF-kappaB during productive infection and this may be an essential aspect of its replication scheme [Patel, A., Hanson, J., McLean, T.I., Olgiate, J., Hilton, M., Miller, W.E., Bachenheimer, S.L., 1998. Herpes simplex type 1 induction of persistent NF-kappa B nuclear translocation increases the efficiency of virus replication. Virology 247, 212-222; Gregory, D., Hargett, D., Holmes, D., Money, E., Bachenheimer, S.L., 2004. Efficient replication by herpes simplex virus type 1 involves activation of the IkappaB kinase-IkappaB-RelA/p65 pathway. J. Virol. 78, 13582-13590]. Electromobility shift assays determined that resveratrol, in a dose dependent and reversible manner, suppressed activation of NF-kappaB in Vero cells infected with HSV-1, HSV-2 and acyclovir resistant HSV-1. Furthermore, resveratrol did not protect IkappaBalpha, a cytoplasmic NF-kappaB inhibitor, from degradation in HSV-1 infected cells. Immunohistochemical studies demonstrated that RelA/p65, a component of the dimeric NF-kappaB complex, translocated to the nucleus of HSV-1 infected cells in the presence of resveratrol. Finally, direct effects on viral transcription and DNA synthesis were evaluated. Real-time RT-PCR analysis showed that resveratrol treatment of infected cells resulted in reductions of mRNA for ICP0, ICP4, ICP8 and HSV-1 DNA polymerase by 2.1-, 3.3-, 3.8- and 3.1-fold, respectively. Plus, mRNA for glycoprotein C, an HSV late gene, was completely absent in the presence of resveratrol. Lastly, quantitative PCR showed that resveratrol significantly blocked HSV DNA synthesis. Cumulatively, these data indicate that resveratrol (i) suppresses HSV induced activation of NF-kappaB within the nucleus and (ii) impairs expression of essential immediate-early, early and late HSV genes and synthesis of viral DNA.
白藜芦醇通过未知机制抑制单纯疱疹病毒（HSV）复制。此前有研究表明，这种抑制作用可能是通过一种对HSV复制至关重要的细胞因子介导的[Docherty, J.J., Fu, M.M., Stiffler, B.S., Limperos, R.J., Pokabla, C.M., DeLucia, A.L., 1999. 白藜芦醇对单纯疱疹病毒复制的抑制作用。抗病毒研究。43, 145 - 155]。在研究了众多细胞因子后，我们发现白藜芦醇可抑制HSV感染细胞中NF-κB（核因子κB）的激活。有报道指出，HSV在增殖性感染过程中会激活NF-κB，这可能是其复制机制的一个重要方面[Patel, A., Hanson, J., McLean, T.I., Olgiate, J., Hilton, M., Miller, W.E., Bachenheimer, S.L., 1998. 单纯疱疹病毒1型诱导持续性NF-κB核转位可提高病毒复制效率。病毒学。247, 212 - 222；Gregory, D., Hargett, D., Holmes, D., Money, E., Bachenheimer, S.L., 2004. 单纯疱疹病毒1型的高效复制涉及IκB激酶-IκB-RelA/p65途径的激活。病毒学杂志。78, 13582 - 13590]。电泳迁移率变动分析表明，白藜芦醇以剂量依赖性和可逆的方式抑制感染HSV-1、HSV-2和阿昔洛韦耐药HSV-1的Vero细胞中NF-κB的激活。此外，白藜芦醇不能保护细胞质中的NF-κB抑制剂IκBα在HSV-1感染细胞中不被降解。免疫组织化学研究表明，二聚体NF-κB复合物的一个组成部分RelA/p65在有白藜芦醇存在的情况下会转位到HSV-1感染细胞的细胞核中。最后，评估了白藜芦醇对病毒转录和DNA合成的直接影响。实时逆转录-聚合酶链反应分析表明，用白藜芦醇处理感染细胞后，ICP0、ICP4、ICP8和HSV-1 DNA聚合酶的mRNA分别减少了2.1倍、3.3倍、3.8倍和3.1倍。此外，在有白藜芦醇存在的情况下，HSV晚期基因糖蛋白C的mRNA完全缺失。最后，定量聚合酶链反应表明白藜芦醇显著阻断了HSV DNA的合成。综合这些数据表明，白藜芦醇（i）抑制HSV诱导的细胞核内NF-κB激活，（ii）损害HSV必需的即刻早期、早期和晚期基因的表达以及病毒DNA的合成。
