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TitleTransient glycan shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques.
Journal, issue, pagesCell Rep, Vol. 44, Issue 6, Page 115848, Year 2025
Publish dateJun 13, 2025
AuthorsDaniel J Morris / Jason Gorman / Tongqing Zhou / Jinery Lora / Andrew J Connell / Hui Li / Weimin Liu / Ryan S Roark / Mary S Campion / John W Carey / Rumi Habib / Yingying Li / Christian L Martella / Younghoon Park / Ajay Singh / Kirsten J Sowers / I-Ting Teng / Shuyi Wang / Neha Chohan / Wenge Ding / Craig Lauer / Emily Lewis / Rosemarie D Mason / Juliette M Rando / Lowrey Peyton / Chaim A Schramm / Kshitij Wagh / Bette Korber / Michael S Seaman / Daniel C Douek / Barton F Haynes / Daniel W Kulp / Mario Roederer / Beatrice H Hahn / Peter D Kwong / George M Shaw /
PubMed AbstractBroadly 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 ...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 cryoelectron microscopy (cryo-EM) structure of RHA10 with the 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 that glycan deletions in infecting SHIVs could induce CD4bs bNAbs. To test this hypothesis, we constructed SHIV.CH505 variants with CD4bs-proximal glycan deletions. Infection of 11 macaques resulted in accelerated CD4bs bNAb responses in 9 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 serve as a model for HIV vaccine design.
External linksCell Rep / PubMed:40516049 / PubMed Central
MethodsEM (single particle)
Resolution4.27 Å
Structure data

47000

9dmb

EMDB-47000, PDB-9dmb:
Rhesus RHA10.01 Fab in complex with HIV-1 Env BG505 DS-SOSIP trimer
Method: EM (single particle) / Resolution: 4.27 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • macaca mulatta (Rhesus monkey)
  • human immunodeficiency virus 1
KeywordsIMMUNE SYSTEM / CD4 / HIV-1 / SHIV / T681 / rhesus macaque

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