The hypoxia-inducible factor 1 alpha (HIF1α) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV), Kaposi sarcoma herpes virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIF1α during the virus life cycle and its biological relevance in the context of host has been challenging due to the lack of animal models for human γHV. To study the role of HIF1α, we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIF1α protein and HIF1α-responsive gene expression in permissive cells. siRNA silencing or drug-inhibition of HIF1α reduce virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia-responsive elements (HREs) such as the viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. We found that the promoter of MHV68 ORF74 is responsive to HIF1α and MHV-68 RTA. Moreover, Intranasal infection of HIF1αLoxP/LoxP mice with MHV68 expressing Cre- recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Low oxygen concentrations accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIF1α plays a critical role in promoting virus replication and reactivation from latency by impacting viral gene expression. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.

中文翻译：

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缺氧诱导因子 1 α 在鼠丙型疱疹病毒 68 (MHV68) 裂解性复制和潜伏期重新激活中的作用。

缺氧诱导因子 1 α (HIF1α) 蛋白和缺氧微环境对于致癌性伽马疱疹病毒 (γHV)、卡波西肉瘤疱疹病毒 (KSHV) 和 Epstein-Barr 病毒 (EBV) 的感染和发病至关重要。然而，由于缺乏人类 γHV 的动物模型，了解 HIF1α 在病毒生命周期中的作用及其在宿主环境中的生物学相关性一直具有挑战性。为了研究 HIF1α 的作用，我们使用了鼠伽马疱疹病毒 68 (MHV68)，这是一种很容易感染实验室小鼠的啮齿动物病原体。我们发现 MHV68 感染会诱导受许可细胞中 HIF1α 蛋白和 HIF1α 响应基因的表达。HIF1α 的 siRNA 沉默或药物抑制会由于病毒基因表达的整体下调而减少病毒的产生。最值得注意的是许多带有缺氧反应元件（HRE）的病毒基因显着减少，例如病毒 G 蛋白偶联受体（vGPCR），已知该基因在 KSHV 感染期间激活 HIF1α 转录活性。我们发现 MHV68 ORF74 的启动子对 HIF1α 和 MHV-68 RTA 有反应。此外，用表达Cre重组酶的MHV68对HIF1αLoxP/LoxP小鼠进行鼻内感染会损害早期急性感染期间的病毒扩增，并影响从小鼠中移植的脾细胞的裂解再激活。低氧浓度加速了 MHV68 感染的脾细胞的裂解再激活并增强了病毒的产生。因此，我们得出结论，HIF1α 通过影响病毒基因表达，在促进病毒复制和潜伏期重新激活方面发挥着关键作用。我们的结果强调了氧传感机制和伽玛疱疹病毒之间相互作用在病毒复制和发病机制中的重要性。