Hull McKenna A, Pritchard Suzanne M, Nicola Anthony V
Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.
J Virol. 2025 Apr 15;99(4):e0009025. doi: 10.1128/jvi.00090-25. Epub 2025 Mar 26.
Herpes simplex virus 1 (HSV-1) gD interaction with the host cell receptor nectin-1 triggers the membrane fusion cascade during viral entry. Potent neutralizing antibodies to gD prevent receptor-binding or prevent gD interaction with gH/gL critical for fusion. HSV has many strategies to evade host immune responses. We investigated the ability of virion envelope gC to protect envelope gD from antibody neutralization. HSV-1 lacking gC was more sensitive to neutralization by anti-gD monoclonal antibodies than a wild-type rescuant virus. gD in the HSV-1 gC-null viral envelope had enhanced reactivity to anti-gD antibodies compared to wild type. Soluble nectin-1 bound similar to HSV-1 particles regardless of the presence of gC in the envelope. However, entry of HSV-1 ΔgC was more sensitive to inhibition by soluble nectin-1 receptor. The viral membrane protein composition of HSV-1 ΔgC is equivalent to that of wild type, suggesting that the lack of gC is responsible for the increased reactivity of gD-specific antibodies and the consequent increased susceptibility to neutralization by those antibodies. Together, the results suggest that gC in the HSV-1 envelope shields both receptor-binding domains and gH/gL-interacting domains of gD from neutralizing antibodies, facilitating HSV cell entry.IMPORTANCEHSV-1 causes lifelong infections. There is no vaccine and no cure. Understanding HSV immune evasion strategies is an important goal. HSV-1 gC is a multi-functional envelope glycoprotein. This study suggests that virion gC physically shields neighboring gD from antibodies, including neutralizing monoclonal antibodies. This mechanism may allow HSV to escape immune detection, promoting HSV infection in the host.
单纯疱疹病毒1型（HSV-1）的糖蛋白D（gD）与宿主细胞受体nectin-1相互作用，在病毒进入过程中触发膜融合级联反应。针对gD的强效中和抗体可阻止受体结合或阻止gD与融合关键的gH/gL相互作用。HSV有多种逃避免疫反应的策略。我们研究了病毒体包膜糖蛋白C（gC）保护包膜gD免受抗体中和的能力。与野生型拯救病毒相比，缺乏gC的HSV-1对抗gD单克隆抗体的中和作用更敏感。与野生型相比，HSV-1 gC缺失病毒包膜中的gD与抗gD抗体的反应性增强。无论包膜中是否存在gC，可溶性nectin-1的结合与HSV-1颗粒相似。然而，HSV-1 ΔgC的进入对可溶性nectin-1受体的抑制更敏感。HSV-1 ΔgC的病毒膜蛋白组成与野生型相当，这表明gC的缺失导致gD特异性抗体反应性增加，进而导致对这些抗体中和作用的敏感性增加。总之，结果表明HSV-1包膜中的gC可保护gD的受体结合域和gH/gL相互作用域免受中和抗体的影响，促进HSV进入细胞。
重要性
HSV-1会引起终身感染。既没有疫苗也无法治愈。了解HSV的免疫逃逸策略是一个重要目标。HSV-1 gC是一种多功能包膜糖蛋白。本研究表明，病毒体gC可物理性地保护邻近的gD免受抗体影响，包括中和单克隆抗体。这种机制可能使HSV逃避免疫检测，促进宿主中的HSV感染。
