Evasion of intrinsic antiviral host cell responses by herpesviruses

早幼粒细胞核体（Promyelocytic nuclear bodies，PML NBs）是一种直径为0.2- 1 μ m的核细胞器， 细胞宿主对病毒感染的防御反应。疱疹病毒表达调节 PML或PML相关蛋白通过多种策略，包括降解PML或 PML NB蛋白的重新定位。PML-疱疹病毒相互作用的后果 体内感染还有待详细研究，主要是因为 许多人类疱疹病毒。鼠γ疱疹病毒68（HV 68）是一种合适的模型 研究病毒宿主相互作用的基本生物学问题，因为它自然感染小鼠。 最近，我们发现HV 68通过蛋白酶体依赖性的蛋白酶体介导PML降解。 PML的缺失导致小鼠成纤维细胞中更稳健的病毒复制。 令人惊讶的是，我们发现HV 68介导的PML降解是由病毒体被膜介导的， 蛋白质ORF 75 c，其与细胞甲酰甘氨酰胺核糖核苷酸酰胺转移酶具有同源性 （FGARAT）酶。此外，我们已经证明ORF 75 c对于产生感染性的 病毒ORF 75同源物在所有的鼻状病毒中是保守的，但迄今为止还没有指定的功能。 我们的研究揭示了这种不寻常的蛋白质在鼻病毒生物学中的潜在作用，并建议 HV 68将是研究PML-疱疹病毒体内相互作用的有用模型。的目标 本研究项目的主要目的是：1）确定ORF 75 c介导PML的机制 降解，2）确定ORF 75 c如何促进病毒复制周期，和3） 确定PML在调节急性和慢性炎症的动力学和幅度中的作用， 体内疱疹病毒感染。我们的研究产生的信息将涉及两个 基本问题。首先，病毒FGARAT蛋白的功能是什么？ 第二，PML在调节急性和/或慢性 体内疱疹病毒感染？γHV 68将是解决这些问题的有益模型系统， 这些方法对于人类疱疹病毒来说是非常困难或不可能的， 尤其是γ疱疹病毒。这项研究的实际应用可能支持这一观点 PML缺陷系统可以在实验或临床试验中提供非常灵敏的病毒感染读数， 诊断工作。此外，增强PML活性的抗病毒疗法可能是可以想象的。 开发最后，靶向ORF 75开发新的抗γ疱疹病毒疗法可能 是一个有益的策略，特别是如果它被发现具有内在的酶功能。

Promyelocytic nuclear bodies (PML NBs) are 0.2-1um nuclear organelles that mediate an intrinsic cellular host defense response against virus infections. Herpesviruses express proteins that modulate PML or PML-associated proteins by a variety of strategies, including degradation of PML or relocalization of PML NB proteins. The consequences of PML-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. Murine gammaherpesvirus 68 (γHV68) is emerging as a suitable model to study basic biological questions of virus host interactions because it naturally infects mice. Recently we have found that γHV68 induces PML degradation through a proteasome-dependent mechanism and that loss of PML results in more robust virus replication in mouse fibroblasts. Surprisingly, we found that γHV68-mediated PML degradation is mediated by the virion tegument protein ORF75c, which shares homology with the cellular formylglycinamide ribotide amidotransferase (FGARAT) enzyme. In addition, we have shown that ORF75c is essential for production of infectious virus. ORF75 homologs are conserved in all rhadinoviruses but so far have no assigned functions. Our studies shed light on a potential role for this unusual protein in rhadinovirus biology and suggest that γHV68 will be a useful model for investigation of PML-herpesvirus interactions in vivo. The goals of this research project are to: 1) determine the mechanism by which ORF75c mediates PML degradation, 2) to determine how ORF75c contributes to the viral replication cycle, and 3) to determine the role of PML in modulating the kinetics and amplitude of acute and chronic herpesvirus infection in vivo. The information generated from our studies will address two fundamental questions. First, what is the function of the viral FGARAT proteins for gammaherpesvirus biology and second, what role does PML have in modulating acute and/or chronic herpesvirus infections in vivo? γHV68 will be a rewarding model system to address these questions in ways that would be significantly more difficult or impossible with human herpesviruses and gammaherpesviruses in particular. Practical applications from this research might support the notion that PML-deficient systems can offer a very sensitive readout for viral infection in experimental or diagnostic work. In addition, antiviral therapies that enhance PML activities could conceivably be developed. Finally, targeting ORF75 for developing novel anti-gammaherpesvirus therapeutics might be a rewarding strategy, especially if it is found to possess intrinsic enzymatic functions.