Initiation and Early Development of Three MPER-Directed Neutralizing Antibody Lineages from an HIV-1-Infected Individual. Homo sapiens

Lineage-based vaccine design is an attractive approach for eliciting broadly neutralizing antibodies (bNAbs) against HIV-1. However, most bNAb lineages studied to date have features indicative of unusual recombination and/or development. From an individual in the prospective RV217 cohort, we identified three lineages of bNAbs targeting the membrane-proximal external region (MPER) of the HIV-1 envelope. Antibodies RV217-VRC42.01, VRC43.01 and VRC46.01 used distinct modes of recognition and neutralized a cross-clade virus panel at 93%, 62%, and 30%, respectively. All three lineages had modest levels of somatic hypermutation, normal CDR H3 lengths, and were initiated by the founder MPER. The broadest lineage, VRC42, was remarkably similar to the known bNAb 4E10. A multimeric immunogen based on the founder MPER activated B cells bearing the unmutated common ancestor of VRC42, and modest maturation of early VRC42 intermediates imparted neutralization breadth. These features suggest VRC42 to be a highly promising template for lineage-based vaccine design.