Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

Morris, D. J.; Gorman, J.; Zhou, T.; Lora, J.; Connell, A. J.; Li, H.; Liu, W.; Roark, R. S.; Campion, M. S.; Carey, J. W.; Habib, R.; Li, Y.; Martella, C. L.; Park, Y.; Singh, A.; Sowers, K. J.; Teng, I.-T.; Wang, S.; Chohan, N.; Ding, W.; Lauer, C.; Lewis, E.; Mason, R. D.; Rando, J. M.; Peyton, L.; Schramm, C. A.; Wagh, K.; Korber, B.; Seaman, M. S.; Douek, D. C.; Haynes, B. F.; Kulp, D. W.; Roederer, M.; Hahn, B. H.; Kwong, P. D.; Shaw, G. M.

doi:10.1101/2024.12.30.630768

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bioRxiv · 10.1101/2024.12.30.630768

Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

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Abstract

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryo-EM structure of RHA10 with HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting glycan deletions in infecting SHIVs could consistently induce CD4bs bNAbs. To test this, we constructed SHIV.CH505.D3 with CD4bs-proximal glycan deletions. Infection of 10 macaques resulted in accelerated CD4bs bNAb responses in 8, compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and thus serve as a model for HIV vaccine design. HighlightsO_LIOut of 115 wildtype HIV-1 Env bearing SHIV infected macaques, only one macaque (T681) developed CD4bs bNAbs C_LIO_LICD4bs bNAbs in macaque T681 recognized Env similarly to previously described CDR-H3 dominated human CD4bs bNAbs and exhibited comparable breadth and potency C_LIO_LITransient CD4bs-proximal glycan deletions in macaque T681 preceded bNAb induction C_LIO_LIA novel SHIV with CD4bs-proximal glycan holes and enhanced CD4bs antigenicity immunofocused B cell responses to the CD4bs and elicited cross-clade neutralizing responses in 80% of macaques C_LI

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Morris, D. J., Gorman, J., Zhou, T., Lora, J., Connell, A. J., Li, H., Liu, W., Roark, R. S., Campion, M. S., Carey, J. W., Habib, R., Li, Y., Martella, C. L., Park, Y., Singh, A., Sowers, K. J., Teng, I.-T., Wang, S., Chohan, N., Ding, W., Lauer, C., Lewis, E., Mason, R. D., Rando, J. M., Peyton, L., Schramm, C. A., Wagh, K., Korber, B., Seaman, M. S., Douek, D. C., Haynes, B. F., Kulp, D. W., Roederer, M., Hahn, B. H., Kwong, P. D., Shaw, G. M.. 2024-12-31. Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques. https://doi.org/10.1101/2024.12.30.630768

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