Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Cell Rep. 2023 Aug 29;42(8):112942. doi: 10.1016/j.celrep.2023.112942. Epub 2023 Aug 9.
Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.
Zika 病毒（ZIKV）是一种新兴病原体，可导致严重的先天性缺陷。ZIKV 和登革热病毒（DENV）在流行病学和免疫交叉反应方面存在重叠，这给疫苗设计带来了复杂的挑战，因为抗体依赖性疾病增强的可能性。因此，ZIKV 特异性抗体靶标的分类具有重要价值。从感染 Zika 病毒的恒河猴中，我们鉴定出 Zika 病毒反应性 B 细胞，并分离出具有与 DENV 无交叉反应的高效中和单克隆抗体（mAbs）。我们将这些 mAbs 分为四个不同的抗原组，针对包膜糖蛋白上的 Zika 病毒特异性跨二聚体表位。代表性 mAbs 与 Zika 病毒包膜糖蛋白复合物的共结晶结构揭示了包膜二聚体表位和独特的二聚体-二聚体表位靶向。在 Zika 病毒感染后的恢复期人类中，所有四个特异性均通过血清学鉴定，来自所有四个组的代表性 mAbs 可预防 Zika 病毒在小鼠中的复制。这些结果提供了 Zika 病毒特异性抗原性的关键见解，并对 Zika 病毒疫苗、诊断和治疗的发展具有重要意义。
