Functional development of a V3-specific broadly neutralizing antibody isolated from a case of HIV superinfection

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. Mature bnAb QA013.2 bound both initial transmitted and superinfecting virus, but its inferred naive bound only the superinfecting strain and was not neutralizing. QA013.2 requires residues spanning FWRH1-CDRH1 to attain breadth, which is uncommon for V3-specific bnAbs. A 4.15 [A] cryo-EM structure of QA013.2 bound to heterologous native-like trimer showed recognition of V3 signatures (N301, N332, and GDIR). Antigenic profiling revealed that viral escape was achieved not only by changes in the structurally-defined epitope, but also by mutations in V1. These results highlight shared and distinct properties of QA013.2 relative to other V3-specific bnAbs in the setting of sequential, diverse antigenic variants.