Molecular Evolution of a Successful Broadly Neutralizing Antibody
Deep sequencing (i.e., the ability to generate millions of independent sequences of a gene product) identifies critical intermediates for the evolution of broadly neutralizing antibodies and guides vaccine development. In Panel A, maximum-likelihood trees of heavy-chain sequences were derived from the IGHV1-2 gene that gives rise to a broadly neutralizing antibody, VRC01, in a representative patient, donor 74, as described previously.23 The donor 74 tree is rooted in the putative reverted unmutated ancestor of the heavy chain of a specific broadly neutralizing CD4-binding site monoclonal antibody, VRC-PG04 (as shown in Panel B, Protein Data Bank code 3SE9). Sequences from other donors are included in the cross-donor phylogenetic analysis. Bars representing 0.1 changes per nucleotide site are shown. Sequences within the shaded box include autologous VRC01-like heavy-chain sequences that neutralize HIV with good potency and breadth and are probably clonal relatives of VRC-PG04. Sequences highlighted in blue and purple represent broadly neutralizing antibodies isolated with structural probes.