Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Med Virol. 2019 May;91(5):820-828. doi: 10.1002/jmv.25384. Epub 2019 Jan 7.
Ocular herpes, caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections, remains an important corneal disease, which may result in loss of vision. Because the frequency of acyclovir resistance in HSV has increased, novel antiviral agents are needed for therapeutic approaches to ocular herpes. Several studies have demonstrated that fusion proteins containing entire ectodomain of HSV glycoprotein D receptors, including herpesvirus entry mediator A (HVEM), nectin-1 and nectin-2, and the Fc portion of human IgG (HVEMIg, nectin-1Ig, and nectin-2Ig, respectively), can exert antiviral effects in vitro and in vivo. Here, to evaluate the antiviral potential of HVEMIg, nectin-1Ig, and nectin-2Ig against ocular infections with HSV, transgenic mice expressing these fusion proteins were ocularly inoculated with HSV-1 and HSV-2. Transgenic mouse lines expressing HVEMIg and nectin-1Ig showed marked resistance to ocular herpes; on the other hand, mouse lines expressing nectin-2Ig did not. Furthermore, to investigate the therapeutic effects of nectin-1Ig, which can neutralize HSVs in vitro against ocular disease, transgenic mouse serum containing nectin-1Ig was dropped into the eyes of wild-type mice after HSV infection. Reduction of severe symptoms could be observed in mice treated with nectin-1Ig serum. These results warrant further study of soluble HVEM and nectin-1 products as preventive and therapeutic agents against ocular herpes caused by HSV-1 and HSV-2 infections, especially nectin-1Ig as a new eye drop.
单纯疱疹病毒 1 型（HSV-1）和 2 型（HSV-2）感染引起的眼部单纯疱疹仍然是一种重要的角膜疾病，可能导致视力丧失。由于 HSV 中阿昔洛韦耐药的频率增加，需要新型抗病毒药物来治疗眼部单纯疱疹。几项研究表明，包含 HSV 糖蛋白 D 受体整个外域的融合蛋白，包括疱疹病毒进入介体 A（HVEM）、神经纤毛蛋白-1 和神经纤毛蛋白-2，以及人 IgG 的 Fc 部分（分别为 HVEMIg、神经纤毛蛋白-1Ig 和神经纤毛蛋白-2Ig），可以在体外和体内发挥抗病毒作用。在这里，为了评估 HVEMIg、神经纤毛蛋白-1Ig 和神经纤毛蛋白-2Ig 对眼部 HSV 感染的抗病毒潜力，用这些融合蛋白转染的转基因小鼠经眼部接种 HSV-1 和 HSV-2。表达 HVEMIg 和神经纤毛蛋白-1Ig 的转基因小鼠品系对眼部单纯疱疹表现出明显的抗性；另一方面，表达神经纤毛蛋白-2Ig 的小鼠品系没有。此外，为了研究神经纤毛蛋白-1Ig 的治疗效果，该融合蛋白可以在体外中和 HSV，在 HSV 感染后将含有神经纤毛蛋白-1Ig 的转基因小鼠血清滴入野生型小鼠的眼睛中。在用神经纤毛蛋白-1Ig 血清治疗的小鼠中可以观察到严重症状的减轻。这些结果表明，可溶性 HVEM 和神经纤毛蛋白-1 产品作为预防和治疗 HSV-1 和 HSV-2 感染引起的眼部单纯疱疹的药物具有进一步研究的价值，特别是神经纤毛蛋白-1Ig 作为一种新型眼药水。
