Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Virus Res. 2012 Aug;167(2):273-84. doi: 10.1016/j.virusres.2012.05.010. Epub 2012 May 23.
Type-I interferon (IFN)-mediated responses are a crucial first line of defense against viral infections and are critical for generating both innate and adaptive immunity. Therefore, viruses have necessarily evolved mechanisms to impede the IFN response. HSV-2 was found to completely abolish type-1 IFN-mediated signaling via multiple STAT2-associated mechanisms. Although the extent and kinetics of this inactivation were indistinguishable between the various cell-lines examined, there were distinct differences in the mechanisms HSV-2 employed to subvert IFN-signaling among the cell-lines. These mechanistic differences could be segregated into two categories dependent on the phase of the HSV replicative cycle that was responsible for this inhibition: (1) early phase-inhibited cells which exhibited abrogation of IFN-signaling prior to viral DNA replication; (2) late phase-inhibited cells where early phase inhibition mechanisms were not functional, but viral functions expressed following DNA replication compensated for their ineffectiveness. In early phase-inhibited cells, HSV-2 infection targeted STAT2 protein for proteosomal degradation and prevented de novo expression of STAT2 by degrading its mRNA. In contrast, HSV-2 infected late phase-inhibited cells exhibited no apparent changes in STAT2 transcript or protein levels. However, in these cells STAT2 was not activated by phosphorylation and failed to translocate to the cell nucleus, thereby preventing transactivation of antiviral genes. In primary human fibroblasts, HSV-2 failed to fully degrade STAT2 and therefore, both early and late phase mechanisms functioned cooperatively to subvert IFN-mediated antiviral gene expression. Taken together, these results indicate the importance that HSV-2 has assigned to STAT2, investing significant genomic currency throughout its replicative lifecycle for continuous targeted destruction and inhibition of this protein.
I 型干扰素（IFN）介导的反应是抵御病毒感染的第一道防线，对于产生先天和适应性免疫至关重要。因此，病毒必然进化出了阻碍 IFN 反应的机制。HSV-2 通过多种与 STAT2 相关的机制完全消除了 I 型 IFN 介导的信号。虽然在检查的各种细胞系中，这种失活的程度和动力学没有区别，但 HSV-2 用于颠覆 IFN 信号的机制在细胞系之间存在明显差异。这些机制差异可以分为两类，取决于负责这种抑制的 HSV 复制周期的阶段：（1）早期相抑制细胞，其在病毒 DNA 复制之前表现出 IFN 信号的阻断；（2）晚期相抑制细胞，其中早期相抑制机制不起作用，但在 DNA 复制后表达的病毒功能补偿了它们的无效性。在早期相抑制细胞中，HSV-2 感染将 STAT2 蛋白靶向蛋白酶体降解，并通过降解其 mRNA 来阻止 STAT2 的从头表达。相比之下，HSV-2 感染的晚期相抑制细胞中 STAT2 的转录本或蛋白水平没有明显变化。然而，在这些细胞中，STAT2 没有被磷酸化激活，也没有转位到细胞核，从而阻止了抗病毒基因的反式激活。在原代人成纤维细胞中，HSV-2 不能完全降解 STAT2，因此，早期和晚期相机制协同作用，颠覆 IFN 介导的抗病毒基因表达。综上所述，这些结果表明 HSV-2 对 STAT2 的重视，在其复制生命周期的整个过程中投入了大量的基因组货币，对该蛋白进行持续的靶向破坏和抑制。
