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

Daniel J Morris et al. bioRxiv. .

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  • Transient glycan shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques.
    Morris DJ, Gorman J, Zhou T, Lora J, Connell AJ, Li H, Liu W, Roark RS, Campion MS, Carey JW, Habib R, Li Y, Martella CL, Park Y, Singh A, Sowers KJ, Teng IT, Wang S, Chohan N, Ding W, Lauer C, Lewis E, Mason RD, Rando JM, Peyton L, Schramm CA, Wagh K, Korber B, Seaman MS, Douek DC, Haynes BF, Kulp DW, Roederer M, Hahn BH, Kwong PD, Shaw GM. Morris DJ, et al. Cell Rep. 2025 Jun 24;44(6):115848. doi: 10.1016/j.celrep.2025.115848. Epub 2025 Jun 13. Cell Rep. 2025. PMID: 40516049 Free PMC article.

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.

Highlights: Out of 115 wildtype HIV-1 Env bearing SHIV infected macaques, only one macaque (T681) developed CD4bs bNAbsCD4bs bNAbs in macaque T681 recognized Env similarly to previously described CDR-H3 dominated human CD4bs bNAbs and exhibited comparable breadth and potencyTransient CD4bs-proximal glycan deletions in macaque T681 preceded bNAb inductionA 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.

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