Roark, R. S.; Habib, R.; Gorman, J.; Li, H.; Connell, A. J.; Bonsignori, M.; Guo, Y.; Hogarty, M. P.; Olia, A. S.; Sowers, K.; Zhang, B.; Bibollet-Ruche, F.; Callaghan, S.; Carey, J. W.; Cerutti, G.; Harris, D. R.; He, W.; Lewis, E.; Liu, T.; Mason, R. D.; Park, Y.; Rando, J. M.; Singh, A.; Wolff, J.; Lei, Q. P.; Louder, M. K.; Doria-Rose, N. A.; Andrabi, R.; Saunders, K. O.; Seaman, M. S.; Haynes, B. F.; Kulp, D. W.; Mascola, J. R.; Roederer, M.; Sheng, Z.; Hahn, B. H.; Shaw, G. M.; Kwong, P. D.; Shapiro, L.

Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition.