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首页> 美国卫生研究院文献>Journal of Virology >Mutations in the N Termini of Herpes Simplex Virus Type 1 and 2 gDs Alter Functional Interactions with the Entry/Fusion Receptors HVEM Nectin-2 and 3-O-Sulfated Heparan Sulfate but Not with Nectin-1
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Mutations in the N Termini of Herpes Simplex Virus Type 1 and 2 gDs Alter Functional Interactions with the Entry/Fusion Receptors HVEM Nectin-2 and 3-O-Sulfated Heparan Sulfate but Not with Nectin-1

机译：1型和2型单纯疱疹病毒N末端的突变改变了与进入/融合受体HVEMNectin-2和3-O-硫酸乙酰肝素硫酸盐的功能相互作用但与Nectin-1无关。

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Multiple cell surface molecules (herpesvirus entry mediator [HVEM], nectin-1, nectin-2, and 3-O-sulfated heparan sulfate) can serve as entry receptors for herpes simplex virus type 1 (HSV-1) or HSV-2 and also as receptors for virus-induced cell fusion. Viral glycoprotein D (gD) is the ligand for these receptors. A previous study showed that HVEM makes contact with HSV-1 gD at regions within amino acids 7 to 15 and 24 to 32 at the N terminus of gD. In the present study, amino acid substitutions and deletions were introduced into the N termini of HSV-1 and HSV-2 gDs to determine the effects on interactions with all of the known human and mouse entry/fusion receptors, including mouse HVEM, for which data on HSV entry or cell fusion were not previously reported. A cell fusion assay was used to assess functional activity of the gD mutants with each entry/fusion receptor. Soluble gD:Fc hybrids carrying each mutation were tested for the ability to bind to cells expressing the entry/fusion receptors. We found that deletions overlapping either or both of the HVEM contact regions, in either HSV-1 or HSV-2 gD, severely reduced cell fusion and binding activity with all of the human and mouse receptors except nectin-1. Amino acid substitutions described previously for HSV-1 (L25P, Q27P, and Q27R) were individually introduced into HSV-2 gD and, for both serotypes, were found to be without effect on cell fusion and the binding activity for nectin-1. Each of these three substitutions in HSV-1 gD enhanced fusion with cells expressing human nectin-2 (ordinarily low for wild-type HSV-1 gD), but the same substitutions in HSV-2 gD were without effect on the already high level of cell fusion observed with the wild-type protein. The Q27P or Q27R substitution in either HSV-1 and HSV-2 gD, but not the L25P substitution, significantly reduced cell fusion and binding activity for both human and mouse HVEM. Each of the three substitutions in HSV-1 gD, as well as the deletions mentioned above, reduced fusion with cells bearing 3-O-sulfated heparan sulfate. Thus, the N terminus of HSV-1 or HSV-2 gD is not necessary for functional interactions with nectin-1 but is necessary for all of the other receptors tested here. The sequence of the N terminus determines whether nectin-2 or 3-O-sulfated heparan sulfate, as well as HVEM, can serve as entry/fusion receptors.
机译：多种细胞表面分子（疱疹病毒进入介体[HVEM]，nectin-1，nectin-2和3-O-硫酸硫酸乙酰肝素）可以用作单纯疱疹病毒1型（HSV-1）或HSV-2和也可作为病毒诱导的细胞融合的受体。病毒糖蛋白D（gD）是这些受体的配体。先前的研究表明，HVEM在gD的N末端7至15和24至32位氨基酸内与HSV-1 gD接触。在本研究中，氨基酸取代和缺失被引入HSV-1和HSV-2 gD的N末端，以确定对与所有已知的人类和小鼠进入/融合受体（包括小鼠HVEM）相互作用的影响，为此HSV进入或细胞融合的数据以前没有报道。细胞融合测定用于评估具有每个进入/融合受体的gD突变体的功能活性。测试携带每个突变的可溶性gD：Fc杂合体与表达进入/融合受体的细胞结合的能力。我们发现，在HSV-1或HSV-2 gD中，与HVEM接触区域中的一个或两个重叠的缺失会严重减少细胞融合和与除nectin-1以外的所有人类和小鼠受体的结合活性。先前描述的HSV-1氨基酸取代（L25P，Q27P和Q27R）被单独引入HSV-2 gD中，并且对于两种血清型，都发现它们对细胞融合和nectin-1的结合活性没有影响。 HSV-1 gD中的这三个取代中的每一个都增强了与表达人nectin-2的细胞的融合（对于野生型HSV-1 gD通常较低），但是HSV-2 gD中的相同取代对已经很高水平的人融合素没有影响细胞与野生型蛋白融合。 HSV-1和HSV-2 gD中的Q27P或Q27R取代，而不是L25P取代，显着降低了人和小鼠HVEM的细胞融合和结合活性。 HSV-1 gD中的三个取代基以及上述缺失均减少了与带有3-O-硫酸化硫酸乙酰肝素的细胞的融合。因此，HSV-1或HSV-2 gD的N末端对于与nectin-1的功能相互作用不是必需的，但对于此处测试的所有其他受体都是必需的。 N末端的序列决定了Nectin-2或3-O-硫酸硫酸乙酰肝素以及HVEM是否可用作进入/融合受体。

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