Effective, broadly neutralizing antibodies (bNAbs) to HIV-1 are observed many years after infection and show unusual features, such as long and protruding heavy-chain CDR3 regions, unusual post-translational modifications and extensive somatic hypermutation (SHM). In Cell, Shapiro and colleagues investigate the ontogeny of the bNAb lineage VRC01, which targets the site of engagement of the coreceptor CD4 by HIV-1, through longitudinal sampling of peripheral B cell transcripts over 15 years and co-crystal structures of members of this lineage. The VCR01 lineage shows very high diversity, due to a high rate of SHM during the course of the infection. The structures indicate that amino acid changes enhance antibody-antigen interactions, while the lineage conserves the binding mode and core interactive residues. SHM persists during the course of infection with rates of about two substitutions per 100 nucleotides per year, comparable to that of HIV-1 evolution. These results suggest that just a few highly diverse antibody lineages may be critical for the control of HIV-1.

Cell (9 April 2015) doi:10.1016/j.cell.2015.03.004