Rapid and Focused Maturation of a VRC01-Class Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan

The VH1-2 restricted VRC01-class of antibodies targeting the HIV Envelope CD4 binding site (CD4bs) are a major focus of HIV vaccine strategies. While enormous progress has been made in the activation of VRC01-class antibody precursors by immunization, challenges remain in understanding how to drive such responses towards the neutralization breadth characteristic of this family of antibodies. To inform these strategies, we describe here the rapid development of a VRC01-class antibody lineage in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies have the hallmark VRC01-class features and demonstrate neutralization breadth similar to the prototype VRC01 antibody but are 3 to 4-fold less mutated. Maturation occurred rapidly within ~24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This first longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.