Rare immunoglobulin insertions after germline-targeting HIV-1 Env vaccination

Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We designed a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activated gl-CH31 naive B cells in knock-in mice and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing revealed selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof-of-concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.