HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

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.

doi:10.1101/2024.06.11.598384

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bioRxiv · 10.1101/2024.06.11.598384

HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

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Abstract

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. HighlightsO_LIIsolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaques C_LIO_LICryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognition C_LIO_LIAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame two C_LIO_LIThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodies C_LIO_LIStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition mode C_LIO_LIPropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naive rhesus repertoire C_LIO_LIDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity C_LI

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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.. 2024-06-12. HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene. https://doi.org/10.1101/2024.06.11.598384

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