Modulation of human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus replication and transcription activator transactivation by interferon regulatory factor 7
Modulation of human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus replication and transcription activator transactivation by interferon regulatory factor 7
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DOI：
10.1128/jvi.79.4.2420-2431.2005
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发表时间：
2005-02-01
影响因子：
5.4
通讯作者：
Wood, C
中科院分区：
文献类型：
--
作者：
Wang, JZ;Zhang, J;Wood, C
人类疱疹病毒 8 (HHV-8)/卡波西肉瘤相关疱疹病毒感染会经历受病毒基因产物调节的裂解期和潜伏期，但对宿主蛋白的参与知之甚少。复制和转录激活剂 (RTA) 是一种病毒蛋白，足以通过激活下游基因来启动裂解复制，包括编码转录后激活剂的病毒早期基因开放阅读框 57 (ORF 57)。在这项研究中，我们证明细胞干扰素调节因子 7 (IRF-7) 通过与 RTA 竞争与 ORF 57 启动子中的 RTA 反应元件结合，从而下调 RTA 诱导的基因表达，从而负向调节这一过程。我们还表明，α 干扰素抑制 RTA 介导的反式激活，并且抑制涉及 IRF-7。我们的研究表明，HHV-8 感染后，宿主会通过 IRF-7 与裂解病毒基因启动子结合来抑制裂解基因表达。这些发现表明，HHV-8 已经开发出一种新的机制来诱导但随后颠覆先天抗病毒反应，特别是干扰素信号通路，以调节 RTA 活性并最终调节病毒潜伏/裂解复制周期。
Human herpesvirus 8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus infection goes through lytic and latent phases that are regulated by viral gene products, but very little is known about the involvement of host proteins. The replication and transcription activator (RTA) is a viral protein sufficient to initiate lytic replication by activating downstream genes, including the viral early gene open reading frame 57 (ORF 57), which codes for a posttranscriptional activator. In this study, we demonstrate that cellular interferon regulatory factor 7 (IRF-7) negatively regulates this process by competing with RTA for binding to the RTA response element in the ORF 57 promoter to down-regulate RTA-induced gene expression. We also show that alpha interferon represses RTA-mediated transactivation and that repression involves IRF-7. Our study indicates that upon HHV-8 infection, the host responds by suppression of lytic gene expression through binding of IRF-7 to the lytic viral gene promoter. These findings suggest that HHV-8 has developed a novel mechanism to induce but then subvert the innate antiviral response, specifically the interferon-signaling pathway, to regulate RTA activity and ultimately the viral latent/lytic replicative cycle.