Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus.
Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus.
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DOI：
10.1128/mbio.00113-16
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发表时间：
2016-03-01
期刊：
影响因子：
6.4
通讯作者：
Miller G
中科院分区：
文献类型：
--
作者：
Gorres KL;Daigle D;Mohanram S;McInerney GE;Lyons DE;Miller G
EB病毒（EBV）从潜伏期重新激活进入其生命周期的裂解期，使病毒能够在细胞之间和宿主之间传播。丙戊酸（VPA）抑制EBV感染的B淋巴瘤细胞裂解周期的启动。虽然VPA阻断病毒裂解基因表达，但它诱导许多细胞基因的表达，因为它是组蛋白脱乙酰酶（HDAC）抑制剂。在这里，我们表明，使用VPA的衍生物，阻断EBV再激活是从HDAC抑制分离。丙戊酰胺（VPM）是丙戊酸的酰胺衍生物，不是HDAC抑制剂，可阻止介导裂解再活化的两种EBV基因BZLF1和BRLF1的表达。VPM也抑制病毒晚期基因的表达，但不是早期基因，当BZLF1外源表达。与VPA不同，VPM不激活卡波西肉瘤相关疱疹病毒的裂解表达。细胞立即早期基因（如FOS和EGR1）的表达在EBV裂解周期的动力学上游。VPM没有激活这些细胞的立即早期基因的表达，但降低其表达水平时，丁酸，HDAC抑制剂诱导。VPM并没有改变其他几个细胞立即早期基因的表达，包括STAT3，这是诱导的HDAC抑制剂在细胞难溶诱导。因此，VPM选择性地抑制病毒和细胞基因表达。VPA和VPM代表了一类新的抗病毒药物。VPA和VPM阻断EBV再激活的机制可能与其抗惊厥活性有关。EB病毒（EBV）是一种人类肿瘤病毒，可造成终身潜伏感染。EBV重新激活进入其生命周期的裂解期，使病毒得以传播。以前，我们发现EBV再活化被丙戊酸（VPA）阻断，丙戊酸是一种细胞组蛋白脱乙酰酶（HDAC）的抑制剂。VPA改变了数千个细胞基因的表达。在这项研究中，我们证明了丙戊酰胺（VPM），一种丙戊酸的酰胺衍生物，不是HDAC抑制剂，可以阻止EBV裂解周期的启动。VPA诱导卡波济肉瘤相关疱疹病毒（KSHV）的裂解再激活，但VPM没有。与VPA不同，VPM不会激活细胞的即刻早期基因表达。VPM是一种新型抗病毒药物。VPM将有助于探索EBV裂解性再激活的机制，并可能具有治疗应用。
Reactivation of Epstein-Barr virus (EBV) from latency into the lytic phase of its life cycle allows the virus to spread among cells and between hosts. Valproic acid (VPA) inhibits initiation of the lytic cycle in EBV-infected B lymphoma cells. While VPA blocks viral lytic gene expression, it induces expression of many cellular genes, because it is a histone deacetylase (HDAC) inhibitor. Here we show, using derivatives of VPA, that blockade of EBV reactivation is separable from HDAC inhibition. Valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented expression of two EBV genes, BZLF1 and BRLF1, that mediate lytic reactivation. VPM also inhibited expression of a viral late gene, but not early genes, when BZLF1 was exogenously expressed. Unlike VPA, VPM did not activate lytic expression of Kaposi’s sarcoma-associated herpesvirus. Expression of cellular immediate-early genes, such as FOS and EGR1, is kinetically upstream of the EBV lytic cycle. VPM did not activate expression of these cellular immediate-early genes but decreased their level of expression when induced by butyrate, an HDAC inhibitor. VPM did not alter expression of several other cellular immediate-early genes, including STAT3, which were induced by the HDAC inhibitors in cells refractory to lytic induction. Therefore, VPM selectively inhibits both viral and cellular gene expression. VPA and VPM represent a new class of antiviral agents. The mechanism by which VPA and VPM block EBV reactivation may be related to their anticonvulsant activity. Epstein-Barr virus, (EBV), a human tumor virus, establishes a life-long latent infection. Reactivation of EBV into the lytic phase of its life cycle allows the virus to spread. Previously, we showed that EBV reactivation was blocked by valproic acid (VPA), an inhibitor of cellular histone deacetylases (HDACs). VPA alters the expression of thousands of cellular genes. In this study, we demonstrate that valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented initiation of the EBV lytic cycle. VPA induced lytic reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV), but VPM did not. Unlike VPA, VPM did not activate cellular immediate-early gene expression. VPM is a new type of antiviral agent. VPM will be useful in probing the mechanism of EBV lytic reactivation and may have therapeutic application.