An effective HIV-1 vaccine will require induction of broadly neutralizing antibodies (bNAbs) that target conserved epitopes on the HIV-1 envelope (Env) glycoprotein. bNAb induction is a multi-step process, beginning with rare germline precursor B cell receptors (BCRs) and progressing through affinity maturation guided by sequential immunogen exposure. Understanding this BCR maturation pathway is essential for rational immunogen design. To inform design strategies targeting the silent face (SF) epitope, we generated chimeric antibodies combining mature and germline elements of the SF-specific bNAb SF10. Using X-ray crystallography, we solved high-resolution structures of mature SF10 (1.8 Å) and an intermediate antibody comprising the germline heavy chain and mature light chain (glHC SF10; 2.35 Å). Structural docking onto a 3.3 Å cryo-EM map of SF10 bound to a clade C DS-SOSIP Env trimer revealed that the germline CDRH1 loop lacked stabilizing contacts with gp120, limiting engagement at the SF epitope. Guided by these insights, we designed and screened libraries of gp120 core immunogens optimized for CDRH1 interactions, identifying B41 GT1.2, a gp120 core protein with over 100-fold improved affinity for glHC SF10. In knock-in mice, B41 GT1.2 successfully stimulated intermediate SF-specific precursors, supporting its potential as a low-barrier priming immunogen. Our findings underscore how structural analysis of intermediate antibodies can recapitulate BCR maturation pathways and enable the design of more effective, germline-targeting immunogens for HIV-1 vaccination.
Olajide et al. (Sun,) studied this question.