Consistent Induction of Broadly Neutralizing HIV Antibodies by a Novel Two-Step Mechanism Informs Immunogen Design
Year: 2025
Type: preprint
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.
Authors: 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 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, Kshitij Wagh, Bette T. Korber, Raiees Andrabi, Max Crispin, Drew Weissman, Pamela J. Bjorkman, Beatrice H. Hahn, George M. Shaw
Institutions: University of Pennsylvania, California Institute of Technology, University of Southampton, Duke University, Duke Medical Center, Scripps Research Institute, Bioqual, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Howard Hughes Medical Institute, Rockefeller University, Beth Israel Deaconess Medical Center, Los Alamos National Laboratory, New Mexico Consortium
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: The University of Southampton - To provide a facility to characterize critical sugar components on HIV vaccine candidates for the Collaboration for AIDS Vaccine Discovery (CAVD), G3189035245, California Institute of Technology - to design new vaccines and therapies to prevent HIV infection, Duke University - to facilitate the discovery and licensure of a safe, effective and practical HIV vaccine, or long-acting biologic intervention, to prevent the acqu..., G569728671, Harnessing SHIVs and Sequential Immunization to Elicit V3 Glycan-Targeted bNAbs against HIV-1, G682378342, Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design, California Institute of Technology - To develop a candidate vaccine that can be advanced to clinical testing that elicits neutralizing antibodies against HIV, particularly the V3 glyca..., G9000073099, G9000094766, G9000126728, G9000235472, G9000314919, G9000353251, SHIV Env-antibody coevolution as a molecular guide to HIV-1 V3 glycan targeted vaccine design, Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens, Induction of protective antibodies for HIV vaccine development, Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies, G928377646
OpenAlex ID: W4414875803