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

Ashwin N. Skelly; Harry B. Gristick; Hui Li; Edem Gavor; Andrew J. Connell; Edward F. Kreider; Lorie Marchitto; Michael P. Hogarty; Maddy L. Newby; Joel D. Allen; Weimin Liu; Anthony P. West; Kasirajan Ayyanathan; Mary S. Campion; Kaitlyn Winters; Colette G. Gordon; Rebecca A Osbaldeston; Macy J Akeley; Yingying Li; Ajay Veer Singh; Kendra Cruickshank; Young-Hoon Park; Chengyan Zhao; Xuduo Li; Khaled Amereh; Elizabeth S. Van Itallie; John W. Carey; Amie Albertus; Andrew T. DeLaitsch; Jennifer R. Keeffe

doi:10.1101/2025.10.06.680687

ImmunologybioRxivOct 6, 2025

Preprint

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

Ashwin N. Skelly iD, Harry B. Gristick iD, Hui Li iD, Edem Gavor iD, Andrew J. Connell iD, Edward F. Kreider iD, Lorie Marchitto iD, Michael P. Hogarty iD, Maddy L. Newby iD, Joel D. Allen iD, Weimin Liu iD, Anthony P. West iD, Kasirajan Ayyanathan iD, Mary S. Campion, Kaitlyn Winters, Colette G. Gordon, Rebecca A Osbaldeston iD, Macy J Akeley iD, Yingying Li iD, Ajay Veer Singh iD, Kendra Cruickshank iD, Young-Hoon Park iD, Chengyan Zhao, Xuduo Li iD, Khaled Amereh iD, , George M. Shaw iD

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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