Antibody Light-Chain-Restricted Recognition of the Site of Immune Pressure in the RV144 HIV-1 Vaccine Trial Is Phylogenetically Conserved

In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid-aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169-recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode. [Display omitted] •HIV-1 Env immunization of rhesus yielded a dominant V2 K169 antibody response•All V2 K169-targeting rhesus antibodies contained LCDR2 ED motifs•The ED motif is structurally prepositioned for K169 recognition prior to maturation•The ED motif is conserved throughout primate phylogeny Antibodies isolated from vaccinees from the RV144 HIV-1 vaccine trial shared a recognition motif encoded in their light chains that targeted a site of immune pressure. Wiehe et al. show that the same recognition motif is used in a dominant antibody response in rhesus macaques immunized with RV144 immunogens.