Consistent Induction of Broadly Neutralizing HIV Antibodies by a Novel Two-Step Mechanism Informs Immunogen Design

Skelly, A. N.; Gristick, H. B.; Li, H.; Gavor, E.; Connell, A. J.; Kreider, E. F.; Marchitto, L.; Hogarty, M. P.; Newby, M. L.; Allen, J. D.; Liu, W.; West, A. P.; Ayyanathan, K.; Campion, M. S.; Winters, K.; Gordon, C. G.; Osbaldeston, R. A.; Akeley, M. J.; Li, Y.; Singh, A.; Cruickshank, K.; Park, Y.; Zhao, C.; Li, X.; Amereh, K.; Van Itallie, E.; Carey, J. W.; Albertus, A.; DeLaitsch, A. T.; Keeffe, J. R.; Lituchy, M. G.; Walsh, A. A.; Morris, D. J.; Habib, R.; Bibollet-Ruche, F.; Mishra, N.; Avillion, G.; Koranda, N. S.; Plante, S. J.; Martella, C. L.; Lora, J.; Wang, E. J. D.; Lewis, M. G

doi:10.1101/2025.10.06.680687

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bioRxiv · 10.1101/2025.10.06.680687

Consistent Induction of Broadly Neutralizing HIV Antibodies by a Novel Two-Step Mechanism Informs Immunogen Design

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Abstract

A major obstacle confronting HIV-1 vaccine and cure research is the lack of an outbred animal model for rapid and consistent induction of broadly neutralizing antibodies (bNAbs). We designed an epitope-focused simian-human immunodeficiency virus (SHIV.5MUT) that elicited broad and potent V3-glycan-targeted antibodies within a year of infection in 14 of 22 macaques compared with 0 of 14 control animals. SHIV.5MUT elicited bNAbs by a novel two-step mechanism, inducing an initial wave of V1-directed antibodies that selected for Envs with shortened, hypoglycosylated V1 loops, which in turn primed V3-glycan bNAb precursors. Rhesus bNAbs were immunogenetically and structurally diverse, closely resembling human V3-glycan bNAbs. Env-bNAb coevolution revealed a diverse repertoire of bNAb precursors and the Env variants that matured them, yielding a molecular blueprint for vaccine design.

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Skelly, A. N., Gristick, H. B., Li, H., Gavor, E., Connell, A. J., Kreider, E. F., Marchitto, L., Hogarty, M. P., Newby, M. L., Allen, J. D., Liu, W., West, A. P., Ayyanathan, K., Campion, M. S., Winters, K., Gordon, C. G., Osbaldeston, R. A., Akeley, M. J., Li, Y., Singh, A., Cruickshank, K., Park, Y., Zhao, C., Li, X., Amereh, K., Van Itallie, E., Carey, J. W., Albertus, A., DeLaitsch, A. T., Keeffe, J. R., Lituchy, M. G., Walsh, A. A., Morris, D. J., Habib, R., Bibollet-Ruche, F., Mishra, N., Avillion, G., Koranda, N. S., Plante, S. J., Martella, C. L., Lora, J., Wang, E. J. D., Lewis, M. G. 2025-10-06. Consistent Induction of Broadly Neutralizing HIV Antibodies by a Novel Two-Step Mechanism Informs Immunogen Design. https://doi.org/10.1101/2025.10.06.680687

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