Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates.
Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates.
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重链 CDR3 工程 B 细胞有助于对 HIV-1 候选疫苗进行体内评估。
DOI：
10.1016/j.immuni.2023.07.003
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发表时间：
2023
期刊：
影响因子：
32.4
通讯作者：
C
中科院分区：
文献类型：
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作者：
He,Wenhui;Ou,Tianling;Skamangas,Nickolas;Bailey,CharlesC;Bronkema,Naomi;Guo,Yan;Yin,Yiming;Kobzarenko,Valerie;Zhang,Xia;Pan,Andi;Liu,Xin;Xu,Jinge;Zhang,Lizhou;Allwardt,AvaE;Mitra,Debasis;Quinlan,Brian;Sanders,RogierW;C
V2-聚糖/顶端广泛中和抗体 (bnAb) 可识别 HIV-1 包膜糖蛋白 (Env) 的封闭四级表位。这种封闭结构对于引发顶端抗体是必要的，并且有助于指导其他 bnAb 类别的成熟。为了比较设计用于维持这种构象的抗原，我们评估了移植了表达顶端bnAb VRC26.25的HCDR3的多种B细胞的小鼠的顶端特异性反应。工程B细胞亲和力成熟，指导VRC26.25本身的改进。我们发现可溶性环境 (SOSIP) 变体在提高抗顶点反应的能力方面存在显着差异。以 mRNA-脂质纳米颗粒形式递送的跨膜 SOSIP (SOSIP-TM) 比多聚化 SOSIP 蛋白引发更有效的中和反应。重要的是，SOSIP-TM 从用预测的 VRC26.25-HCDR3 祖细胞工程化的 B 细胞中引发了中和血清，该细胞的亲和力也成熟了。我们的数据表明，HCDR3 编辑的 B 细胞有助于有效地进行 Env 抗原的体内比较，并凸显了以 HCDR3 为重点的疫苗方法的潜力。
V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficientin vivocomparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.