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 Morris, Rumi Habib, Frédéric Bibollet‐Ruche, Nitesh Mishra, Gabriel Avillion, Nicholas 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 Wiehe, Barton F. Haynes, Kshitij Wagh, Bette Korber, Raiees Andrabi, Max Crispin, Drew Weissman, Pamela J. Björkman, Beatrice H. Hahn, George M. Shaw
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 envelope (Env) glycoprotein variants 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.