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

此前，我们发现HSV-1在羊膜细胞株FL感染的早期(几小时后)抑制了干扰素(IFN)信号通路。在本研究中，我们探讨了单纯疱疹病毒1型感染过程中干扰素信号转导抑制的分子机制。在HSV-1感染的早期(1h内)观察到宿主JAK/STAT途径负调控因子细胞因子信号转导抑制因子3(SOCS3)的表达上调。SOCS3的诱导有助于抑制干扰素信号转导。SOCS3的诱导性因细胞系而异。高应答者，如Fland T细胞系CCRF-CEM，显示病毒快速复制并导致裂解性感染。而无应答的单核细胞株U937、THP-1和B细胞株Akata对干扰素信号转导无抑制作用，可持续或延长感染，持续产生低滴度的感染性病毒，HSV-1感染后立即通过STAT3激活诱导SOCS3。JAK3抑制剂WHI-P131可抑制STAT3的磷酸化和SOCS3的诱导。用WHI-P131处理或转染SOCS3特异性反义寡核苷酸可显著抑制HSV-1在FL细胞中的复制。一系列证据表明，单纯疱疹病毒1型感染诱导SOCS3是一个重要的宿主细胞因子，决定了单纯疱疹病毒1型高效复制的细胞类型特异性。诱导SOCS3的作用可能是抑制干扰素信号，从而产生宿主细胞的抗病毒状态。此外，抑制SOCS3可以抑制HSV-1的复制，因此它应该成为抗病毒感染的治疗药物的新靶点。

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.