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bioRxiv : the preprint server for biology · 2025

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

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Skelly Ashwin N, Gristick Harry B, Li Hui, Gavor Edem, Connell Andrew J, Kreider Edward F, Marchitto Lorie, Hogarty Michael P, Newby Maddy L, Allen Joel D, Liu Weimin, West Anthony P, Ayyanathan Kasirajan, Campion Mary S, Winters Kaitlyn, Gordon Colette G, Osbaldeston Rebecca A, Akeley Macy J, Li Yingying, Singh Ajay, Cruickshank Kendra, Park Younghoon, Zhao Chengyan, Li Xuduo, Amereh Khaled, Itallie Elizabeth Van, Carey John W, Albertus Amie, DeLaitsch Andrew T, Keeffe Jennifer R, Lituchy Melinda G, Walsh Agnes A, Morris Daniel J, Habib Rumi, Bibollet-Ruche Frederic, Mishra Nitesh, Avillion Gabriel, Koranda Nicholas S, Plante Samantha J, Martella Christian L, Lora Jinery, Wang Eric J D, Lewis Mark G, Martin Malcolm A, Nussenzweig Michel C, Seaman Michael S, Irvine Darrell J, Wiehe Kevin J, Haynes Barton F, Wagh Kshitij, Korber Bette T, Andrabi Raiees, Crispin Max, Weissman Drew, Bjorkman Pamela J, Hahn Beatrice H, Shaw George M

Аннотация

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.