Induction of broadly neutralizing HIV antibodies by a two-step mechanism informs vaccine 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
- Emily Lewis
- Yingying Li
- Ajay Singh
- Kendra Cruickshank
- Younghoon Park
- Chengyan Zhao
- Xuduo Li
- Khaled Amereh
- Elizabeth Van Itallie
- John W. Carey
- Amie Albertus
- Andrew T. DeLaitsch
- Jennifer R. Keeffe
- Melinda G. Lituchy
- Agnes A. Walsh
- Daniel J. Morris
- Rumi Habib
- Frederic Bibollet-Ruche
- Nitesh Mishra
- Gabriel Avillion
- Nicholas S. Koranda
- Samantha J. Plante
- Christian L. Martella
- Jinery Lora
- Eric J. D. Wang
- Mark G. Lewis
- Malcolm A. Martin
- Michel C. Nussenzweig
- Michael S. Seaman
- Darrell J. Irvine
- Kevin J. Wiehe
- Barton F. Haynes
2026-05-07
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 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.