Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.

HIV-1包膜糖蛋白免疫原诱导广泛中和抗体（bNAb）将是朝着有效疫苗迈出的重要一步。此过程中的关键步骤是激活表达具有可能进化为bNAb的种系（gl）抗体前体的幼稚B细胞的激活。在这里，我们重新设计了BG505 SOSIP.664糖蛋白，使其与靶向三聚体顶点或CD4结合位点的bNAbs的gl前体结合。所得的BG505 SOSIP.v4.1-GT1三聚体在体外与多种bNAb gl gl前体结合。表达gl-VRC01或gl-PGT121的基因敲入小鼠的免疫实验表明，该三聚体在体内激活B细胞，导致特异性抗体分泌到血清中。靶向gl的三聚体的晶体结构为3。