The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attributes of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells
The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attributes of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells
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DOI：
10.1128/jvi.72.12.9992-10002.1998
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发表时间：
1998-12-01
影响因子：
5.4
通讯作者：
Campadelli-Fiume, G
中科院分区：
文献类型：
--
作者：
Cocchi, F;Menotti, L;Campadelli-Fiume, G
我们报告了免疫球蛋白（Ig）超家族中迄今为止未知的成员的功能性克隆，该成员因其能够赋予高度耐药细胞系（J1.1-2细胞）单纯疱疹病毒（HSV）感染的易感性而被选择，该细胞系是通过将BHKtk-细胞暴露于表达肿瘤坏死因子α的重组HSV-1而衍生的 （肿瘤坏死因子-α）。疱疹病毒 Ig 样受体 (HIgR) 的序列预测一种跨膜蛋白，其胞外域由三个半胱氨酸括号结构域（一个 V 样和两个 C 样）组成。 HIgR 与先前描述的蛋白 PRR-1（脊髓灰质炎病毒受体相关蛋白）共享其胞外域，并且似乎是其替代剪接变体。 HIgR 和 PRR-1 均赋予 J1.1-2 细胞对 HSV-1、HSV-2 和牛疱疹病毒 1 的易感性。HIgR 和 PRR-1 的病毒配体是糖蛋白 D，糖蛋白 D 是病毒体包膜的组成部分，长期以来已知可通过与细胞受体分子相互作用介导病毒进入细胞。最近，PRR-1（更名为 HveC（疱疹病毒进入介体 C）和相关的 PRR-5 更名为 HveB）被报道介导 HSV-1、HSV-2 和牛疱疹病毒 1 的进入，并且同源脊髓灰质炎病毒受体被报道介导伪狂犬病病毒的进入（R. J. Geraghty、C. Krummenacher、G. H. Cohen、R. J. Eisenberg 和 P. G. Spear，《科学》280：1618-1620，1998 年； M.S. 华纳、R.J. 杰拉蒂、W.M. Martinez、R. I. Montgomery、J. C. Whitbeck、R. Xu、R. J. Eisenberg、G. H. Cohen 和 P. G. Spear，《病毒学》246：179-189，1998）。在这里，我们进一步表明，使用 PRR-1 单克隆抗体检测到的 HIgR 或 PRR-1 蛋白广泛分布于易受 HSV 感染的人类细胞系中，常用于 HSV 研究。单克隆抗体中和了转染 HIgR 或 PRR-1 cDNA 的细胞以及人类细胞系中的病毒体感染性，表明病毒体与受体分子直接相互作用，并初步将该功能定位到 HIgR 和 PRR-1 的胞外域。 Northern印迹分析显示HIgR或PRR-1 mRNA在人体组织中表达，其中在神经系统样本中检测到最高表达。 HIgR 为 Ig 超家族成员增添了一个新成员，能够介导 α 疱疹病毒进入细胞。 HIgR 或 PRR-1 蛋白在易受 HSV 感染的人类细胞系中广泛分布，加上抗体在相同细胞中的中和活性，直接证明了该分子簇在人类细胞系中作为 HSV-1 和 HSV-2 进入受体的实际用途。神经系统样本中的高水平表达使得这些蛋白质很有可能在人体组织中得到利用。因此，该分子簇可以被认为构成HSV-1和HSV-2的真正受体。
We report on the functional cloning of a hitherto unknown member of the immunoglobulin (Ig) superfamily selected for its ability to confer susceptibility to herpes simplex virus (HSV) infection on a highly resistant cell line (J1. 1-2 cells), derived by exposure of BHKtk- cells to a recombinant HSV-1 expressing tumor necrosis factor alpha (TNF-alpha). The sequence of herpesvirus Ig-like receptor (HIgR) predicts a transmembrane protein with an ectodomain consisting of three cysteine-bracketed domains, one V-like and two C-like. HIgR shares its ectodomain with and appears to be an alternative splice variant of the previously described protein PRR-1 (poliovirus receptor-related protein). Both HIgR and PRR-1 conferred on J1.1-2 cells susceptibility to HSV-1, HSV-2, and bovine herpesvirus 1. The viral ligand of HIgR and PRR-1 is glycoprotein D, a constituent of the virion envelope long known to mediate viral entry into cells through interaction with cellular receptor molecules. Recently, PRR-1, renamed HveC (herpesvirus entry mediator C), and the related PRR-5 renamed HveB, were reported to mediate the entry of HSV-1, HSV-2, and bovine herpesvirus 1, and the homologous poliovirus receptor was reported to mediate the entry of pseudorabies virus (R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, and P. G. Spear, Science 280:1618-1620, 1998; M. S. Warner, R. J. Geraghty, W.M. Martinez, R. I. Montgomery, J. C. Whitbeck, R. Xu, R. J. Eisenberg, G. H. Cohen, and P. G. Spear, Virology 246:179-189, 1998). Here we further show that HIgR or PRR-1 proteins detected by using a monoclonal antibody to PRR-1 are widely distributed among human cell lines susceptible to HSV infection and commonly used for HSV studies. The monoclonal antibody neutralized virion infectivity in cells transfected with HIgR or PRR-1 cDNA, as well as in the human cell lines, indicating a direct interaction of virions with the receptor molecule, and preliminarily mapping this function to the ectodomain of HIgR and PRR-1. Northern blot analysis showed that HIgR or PRR-1 mRNAs were expressed in human tissues, with the highest expression being detected in nervous system samples. HIgR adds a novel member to the cluster of Ig superfamily members able to mediate the entry of alphaherpesviruses into cells. The wide distribution of HIgR or PRR-1 proteins among human cell lines susceptible to HSV infection, coupled with the neutralizing activity of the antibody in the same cells, provides direct demonstration of the actual use of this cluster of molecules as HSV-1 and HSV-2 entry receptors in human cell lines. The high level of expression in samples from nervous system makes the use of these proteins in human tissues very likely. This cluster of molecules may therefore be considered to constitute bona fide receptors for HSV-1 and HSV-2.