Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-borne zoonotic virus, with a 30% case fatality rate in humans. Structural information on the CCHFV membrane fusion glycoprotein Gc–the main target of the host neutralizing antibody response–and on antibody-mediated neutralization mechanisms are lacking. Here we describe the structure of pre-fusion Gc bound to the antigen-binding fragments of two neutralizing antibodies displaying synergy when combined, as well as the structure of trimeric, post-fusion Gc. The structures show the two Fabs acting in concert to block membrane fusion: one targeting the fusion loops and the other blocking Gc trimer formation. The structures also revealed the neutralization mechanism of previously reported anti-CCHFV antibodies, providing the molecular underpinnings essential for developing CCHFV-specific medical countermeasures for epidemic preparedness. The elucidation of antibody neutralization mechanisms of a highly pathogenic virus provides a foundation for epidemic preparedness.

克里米亚-刚果出血热病毒（CCHFV）是传播最广泛的蜱传人畜共患病病毒，人类感染后的病死率为30%。目前缺乏关于CCHFV膜融合糖蛋白Gc（宿主中和抗体反应的主要靶点）以及抗体介导的中和机制的结构信息。在此，我们描述了与两种中和抗体的抗原结合片段结合的融合前Gc的结构（这两种抗体联合使用时具有协同作用），以及三聚体融合后Gc的结构。这些结构显示两种抗体片段（Fabs）协同作用以阻断膜融合：一种靶向融合环，另一种阻断Gc三聚体形成。这些结构还揭示了先前报道的抗CCHFV抗体的中和机制，为研发针对CCHFV的疫情防控医疗对策提供了必要的分子基础。 一种高致病性病毒的抗体中和机制的阐明为疫情防控提供了基础。