Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
Immunity. 2023 Nov 14;56(11):2602-2620.e10. doi: 10.1016/j.immuni.2023.10.009.
Human cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we analyzed the human B cell response of four HCMV top neutralizers from a cohort of 9,000 individuals. By single-cell analyses of memory B cells targeting the pentameric and trimeric HCMV surface complexes, we identified vulnerable sites on the shared gH/gL subunits as well as complex-specific subunits UL and gO. Using high-resolution cryogenic electron microscopy, we revealed the structural basis of the neutralization mechanisms of antibodies targeting various binding sites. Moreover, we identified highly potent antibodies that neutralized a broad spectrum of HCMV strains, including primary clinical isolates, that outperform known antibodies used in clinical trials. Our study provides a deep understanding of the mechanisms of HCMV neutralization and identifies promising antibody candidates to prevent and treat HCMV infection.
人巨细胞病毒（HCMV）可导致胎儿、新生儿和免疫功能低下者发生严重疾病。目前尚无批准的疫苗，且治疗选择有限。在这里，我们分析了来自 9000 个人队列的 4 种 HCMV 顶级中和抗体的人类 B 细胞反应。通过针对五聚体和三聚体 HCMV 表面复合物的记忆 B 细胞的单细胞分析，我们确定了共享 gH/gL 亚基以及特异性亚基 UL 和 gO 上的脆弱位点。使用高分辨率低温电子显微镜，我们揭示了针对各种结合位点的中和抗体的中和机制的结构基础。此外，我们还鉴定了具有广谱中和活性的高效抗体，可中和包括原发性临床分离株在内的多种 HCMV 株，其效果优于临床试验中使用的已知抗体。我们的研究深入了解了 HCMV 中和的机制，并确定了有希望的抗体候选物，以预防和治疗 HCMV 感染。
