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

: 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. 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.