Slein Matthew D, Backes Iara M, Kelkar Natasha S, Garland Callaghan R, Khanwalkar Urjeet S, Sholukh Anton M, Johnston Christine M, Leib David A, Ackerman Margaret E
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA.
bioRxiv. 2024 Nov 22:2024.11.20.624598. doi: 10.1101/2024.11.20.624598.
Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules, allowing the virus to escape immune clearance. In addition to their role in neuropathogenesis and cell-cell spread, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG and promote evasion of humoral immune responses. While monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of the vFcR on mAb-mediated protection by binding to IgG is unknown. Using HSV-1 with intact and ablated gE-mediated IgG Fc binding, and Fc-engineered antibodies with modified ability to interact with gE/gI, we investigated the role of the vFcR in viral pathogenesis and mAb-mediated protection from nHSV. The gD-specific human mAb HSV8 modified to lack binding to gE exhibited enhanced neutralization and protection compared to its native IgG1 form. This improved protection by the engineered mAbs was dependent on the presence of the vFcR. Human IgG3 allotypes lacking vFcR binding also exhibited enhanced antiviral activity , suggesting that vaccines that robustly induce IgG3 responses could show enhanced protection. suggesting the value of vaccination strategies that robustly induce this subclass. Lastly, analysis of longitudinal responses to acute primary genital infection in humans raised the possibility that unlike most viruses, HSV may exhibited slow induction of IgG3. In summary, this study demonstrates that mAbs lacking the ability to interact with the vFcR can exhibit improved protection from HSV-offering new prospects for antibody-based interventions.
单纯疱疹病毒（HSV）编码的表面糖蛋白是宿主防御逃避分子，使病毒能够逃避免疫清除。除了在神经发病机制和细胞间传播中的作用外，糖蛋白E和I（gE/gI）形成了针对人类IgG的大多数亚类和同种异型的病毒Fc受体（vFcR），并促进体液免疫反应的逃避。虽然单克隆抗体（mAb）可保护小鼠免受新生儿HSV（nHSV）感染，但vFcR通过与IgG结合对mAb介导的保护作用尚不清楚。我们使用具有完整和缺失gE介导的IgG Fc结合功能的HSV-1，以及与gE/gI相互作用能力经过修饰的Fc工程抗体，研究了vFcR在病毒发病机制和mAb介导的对nHSV的保护中的作用。与天然IgG1形式相比，经修饰而缺乏与gE结合能力的gD特异性人单克隆抗体HSV8表现出增强的中和作用和保护作用。工程化单克隆抗体这种增强的保护作用取决于vFcR的存在。缺乏vFcR结合能力的人类IgG3同种异型也表现出增强的抗病毒活性，这表明能够强烈诱导IgG3反应的疫苗可能具有增强的保护作用。这表明了能强烈诱导该亚类反应的疫苗接种策略的价值。最后，对人类急性原发性生殖器感染的纵向反应分析提出了一种可能性，即与大多数病毒不同，HSV可能对IgG3的诱导较慢。总之，本研究表明，缺乏与vFcR相互作用能力的单克隆抗体对HSV可表现出增强的保护作用——为基于抗体的干预措施提供了新的前景。
