Modulation of host cell signal transduction pathway by HSV-1 infection

以前，我们发现HSV-1抑制干扰素（IFN）信号通路在羊膜细胞系FL在感染的早期阶段（几个小时后）。在这项研究中，我们研究了干扰素（IFN）信号转导抑制HSV-1感染的分子机制。在HSV-1感染的早期（1小时内）观察到宿主JAK/ STAT途径负调节因子、细胞因子信号传导抑制因子-3（SOCS 3）的上调。SOCS 3的诱导表达在不同细胞系中存在差异。高应答者，如FLand T细胞系CCRF-CEM，显示出快速的病毒复制并导致裂解性感染。另一方面，无应答者，如单核细胞系U937和THP-1，以及B细胞系AKATA，没有表现出IFN信号转导的抑制，并且导致持续或延长的感染，持续产生低滴度的感染性病毒。STAT 3磷酸化和SOCS 3诱导均被Jak 3抑制剂WHI-P131抑制。用WHI-P131处理或转染SOCS 3特异性反义寡核苷酸显著抑制FL细胞中HSV-1的复制。在中和性抗IFN-α/β抗体的存在下，抑制部分被释放。一系列证据表明，HSV-1感染诱导SOCS 3是决定HSV-1有效复制的细胞类型特异性的重要宿主细胞因素。诱导的SOCS 3的作用被认为是抑制IFN信号传导，这产生宿主细胞的抗病毒状态。此外，SOCS 3的抑制可以抑制HSV-1的复制，因此它应该是一个新的靶点，用于治疗病毒感染的药物。

Previously, we found that HSV-1 suppressed interferon (IFN) signaling pathway in amnion cell line FLduring early phase of (a couple of hours after) infection. In this study, we examined the molecular mechanism of suppression of interferon (IFN) signal transduction during HSV-1 infection. Upregulation of a host JAK/ STAT pathway negative regulator, suppressor of cytokine signaling-3 (SOCS3), was observed during early stage (within 1 h) of HSV-1 infection. The induced SOCS3 contributed to suppression of IFN signaling.Inducibility of SOCS3 was varied among cell lines. High responders, such as FLand T cell line CCRF-CEM, showed rapid viral replication and resulted in a lytic infection. On the other hand, non-responders, such as monocytic cell line U937 and THP-1, and Bcell line AKATA, showed no suppression of IFN signal transduction and resulted in a persistent or prolonged infection with continuous production of infectious virus with a low titer.The induction of SOCS3 by HSV-1 should occur via STAT3 activation immediately after HSV-1 infection. Both STAT3 phosphorylation and SOCS3 induction were inhibited by Jak3 inhibitor, WHI-P131. Treatment with WHI-P131 or transfection of antisense oligonucleotides specific for SOCS3 dramatically suppressed replication of HSV-1 in FLcells. The suppression was partially released in the presence of neutralizing anti-IFN-α/β antibodies.Lines of evidence indicate that induction of SOCS3 by HSV-1 infection is a important host cell factor determining cell-type specificity of efficient HSV-1 replication. Role of the induced SOCS3 is suggested to be suppression of the IFN signaling, which generates antiviral state of host cells. Furthermore, inhibition of SOCS3 can suppress HSV-1 replication, so it should be a novel target for therapeutic agent against viral infection.