François Sylvie, Sen Nandini, Mitton Bryan, Xiao Xiangshu, Sakamoto Kathleen M, Arvin Ann
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA Division of Hematology/Oncology, Stanford University School of Medicine, Stanford, California, USA.
J Virol. 2016 Sep 12;90(19):8686-97. doi: 10.1128/JVI.00920-16. Print 2016 Oct 1.
Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella upon primary infection and zoster upon reactivation from latency in sensory ganglion neurons. The replication of herpesviruses requires manipulation of cell signaling pathways. Notably, CREB, a factor involved in the regulation of several cellular processes, is activated upon infection of T cells with VZV. Here, we report that VZV infection also induced CREB phosphorylation in fibroblasts and that XX-650-23, a newly identified inhibitor of the phosphorylated-CREB (pCREB) interaction with p300/CBP, restricted cell-cell spread of VZV in vitro CREB phosphorylation did not require the viral open reading frame 47 (ORF47) and ORF66 kinases encoded by VZV. Evaluating the biological relevance of these observations during VZV infection of human skin xenografts in the SCID mouse model of VZV pathogenesis showed both that pCREB was upregulated in infected skin and that treatment with XX-650-23 reduced infectious-virus production and limited lesion formation compared to treatment with a vehicle control. Thus, processes of CREB activation and p300/CBP binding are important for VZV skin infection and may be targeted for antiviral drug development.
Varicella-zoster virus (VZV) is a common pathogen that causes chicken pox and shingles. As with all herpesviruses, the infection is acquired for life, and the virus can periodically reactivate from latency. Although VZV infection is usually benign with few or no deleterious consequences, infection can be life threatening in immunocompromised patients. Otherwise healthy elderly individuals who develop zoster as a consequence of viral reactivation are at risk for postherpetic neuralgia (PHN), a painful and long-lasting complication. Current vaccines use a live attenuated virus that is usually safe but cannot be given to many immunodeficient patients and retains the capacity to establish latency and reactivate, causing zoster. Antiviral drugs are effective against severe VZV infections but have little impact on PHN. A better understanding of virus-host cell interactions is relevant for developing improved therapies to safely interfere with cellular processes that are crucial for VZV pathogenesis.
水痘带状疱疹病毒（VZV）是一种α疱疹病毒，初次感染时引起水痘，从感觉神经节神经元潜伏状态重新激活时引起带状疱疹。疱疹病毒的复制需要操纵细胞信号通路。值得注意的是，CREB是一种参与多种细胞过程调节的因子，在VZV感染T细胞时被激活。在此，我们报告VZV感染也可诱导成纤维细胞中CREB磷酸化，并且XX - 650 - 23是一种新鉴定的磷酸化CREB（pCREB）与p300/CBP相互作用的抑制剂，它在体外限制了VZV的细胞间传播。CREB磷酸化不需要VZV编码的病毒开放阅读框47（ORF47）和ORF66激酶。在VZV发病机制的SCID小鼠模型中评估人皮肤异种移植VZV感染期间这些观察结果的生物学相关性，结果显示在感染的皮肤中pCREB上调，并且与载体对照处理相比，用XX - 650 - 23处理可降低感染性病毒产生并限制损伤形成。因此，CREB激活和p300/CBP结合过程对VZV皮肤感染很重要，可能成为抗病毒药物开发的靶点。
水痘带状疱疹病毒（VZV）是引起水痘和带状疱疹的常见病原体。与所有疱疹病毒一样，感染终身携带，病毒可从潜伏状态周期性重新激活。虽然VZV感染通常是良性的，几乎没有或没有有害后果，但在免疫功能低下的患者中感染可能危及生命。因病毒重新激活而发生带状疱疹的其他健康老年人有患带状疱疹后神经痛（PHN）的风险，这是一种疼痛且持久的并发症。目前的疫苗使用减毒活病毒，通常是安全的，但不能给予许多免疫缺陷患者，并且保留了建立潜伏和重新激活的能力，从而导致带状疱疹。抗病毒药物对严重的VZV感染有效，但对PHN影响不大。更好地理解病毒与宿主细胞的相互作用对于开发改进的疗法以安全地干扰对VZV发病机制至关重要的细胞过程具有重要意义。
