美国波士顿儿童医院Michael Farzan小组发现，重链CDR3工程化B细胞有助于体内评估HIV-1候选疫苗。2023年8月1日，《免疫》杂志在线发表了这项成果。

研究人员表示，V2-糖蛋白/apex广泛中和抗体（bnAb）可识别HIV-1包膜糖蛋白（Env）的一个封闭的四元表位。这种封闭结构是激发apex抗体的必要条件，也有助于指导其他bnAb类的成熟。

为了比较为保持这种构象而设计的抗原，研究人员在接种了不同B细胞的小鼠体内评估了apex特异性反应，这些B细胞表达apex bnAb VRC26.25的HCDR3。设计的B细胞亲和成熟引导了VRC26.25自身的改进。研究人员发现，可溶性Env（SOSIP）变体在引起抗apex反应的能力上存在显著差异。与多聚化SOSIP蛋白相比，以mRNA-脂质纳米颗粒形式递送的跨膜SOSIP（SOSIP-TM）能引起更强的中和反应。重要的是，SOSIP-TM还能诱导由预测的VRC26.25-HCDR3祖细胞设计的B细胞产生中和血清，这种B细胞也能亲和成熟。

这些数据表明，经HCDR3修饰的B细胞可促进Env抗原在体内的有效比较，并凸显了以HCDR3为重点的疫苗方法的潜力。

附：英文原文

Title: Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

Author: Wenhui He, Tianling Ou, Nickolas Skamangas, Charles C. Bailey, Naomi Bronkema, Yan Guo, Yiming Yin, Valerie Kobzarenko, Xia Zhang, Andi Pan, Xin Liu, Jinge Xu, Lizhou Zhang, Ava E. Allwardt, Debasis Mitra, Brian Quinlan, Rogier W. Sanders, Hyeryun Choe, Michael Farzan

Issue&Volume: 2023-08-01

Abstract: V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternaryepitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessaryto elicit apex antibodies and useful to guide the maturation of other bnAb classes.To compare antigens designed to maintain this conformation, we evaluated apex-specificresponses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvementof VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantlyin their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) deliveredas an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerizedSOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineeredwith the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our datashow that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccineapproach.

DOI: 10.1016/j.immuni.2023.07.003

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00316-3