Evasion of cellular antiviral responses by human cytomegalovirus TRS1 and IRS1
Evasion of cellular antiviral responses by human cytomegalovirus TRS1 and IRS1
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DOI：
10.1128/jvi.78.1.197-205.2004
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发表时间：
2004-01-01
影响因子：
5.4
通讯作者：
Geballe, AP
中科院分区：
文献类型：
--
作者：
Child, SJ;Hakki, M;Geballe, AP
在人巨细胞病毒（HCMV）感染期间，即使病毒蛋白大量合成，细胞蛋白合成仍在继续。因此，HCMV可能具有通过关闭翻译来抵消宿主细胞抗病毒途径的机制。与此观点一致，人成纤维细胞的HCMV感染拯救了缺乏双链RNA结合蛋白基因E3 L（VVDeltaE 3L）的痘苗病毒突变体的复制。HCMV还阻止真核翻译起始因子eIF-2 α的磷酸化、RNA酶L的活化以及病毒和细胞蛋白质合成的关闭，否则这些蛋白质合成是由VVDeltaE 3L感染引起的。为了鉴定引起这些效应的HCMV基因，我们制备了含有HCMV基因组片段的VVDeltaE 3L重组体文库。通过感染nonpermissive细胞与此库和筛选W基因的表达和复制，我们分离出一种病毒，其中含有一个2.8 kb的HCMV片段，拯救VVDeltaE 3L的复制。该片段包含贯穿整个TRS 1基因的J1 S开放阅读框的3'末端。对其他VVDeltaE 3L重组体的分析显示，由TRS 1、pTRS 1以及密切相关的IRS 1基因编码的蛋白质拯救了VVDeltaE 3L复制并防止蛋白质合成的关闭、eIF-2 α的磷酸化和RNase L的激活。这些结果表明，TRS 1和IRS 1能够抵消关键的宿主细胞抗病毒反应途径。
During infection with human cytomegalovirus (HCMV), cellular protein synthesis continues even as viral proteins are being synthesized in abundance. Thus, HCMV may have a mechanism for counteracting host cell antiviral pathways that act by shutting off translation. Consistent with this view, HCMV infection of human fibroblasts rescues the replication of a vaccinia virus mutant lacking the double-stranded RNA-binding protein gene E3L (VVDeltaE3L). HCMV also prevents the phosphorylation of the eukaryotic translation initiation factor eIF-2alpha, the activation of RNase L, and the shutoff of viral and cellular protein synthesis that otherwise result from VVDeltaE3L infection. To identify the HCMV gene(s) responsible for these effects, we prepared a library of VVDeltaE3L recombinants containing HCMV genomic fragments. By infecting nonpermissive cells with this library and screening for W gene expression and replication, we isolated a virus containing a 2.8-kb HCMV fragment that rescues replication of VVDeltaE3L. The fragment comprises the 3' end of the J1S open reading frame through the entire TRS1 gene. Analyses of additional VVDeltaE3L recombinants revealed that the protein encoded by TRS1, pTRS1, as well as the closely related IRS1 gene, rescues VVDeltaE3L replication and prevent the shutoff of protein synthesis, the phosphorylation of eIF-2alpha, and activation of RNase L. These results demonstrate that TRS1 and IRS1 are able to counteract critical host cell antiviral response pathways.