Rumi Habib, Ryan S. Roark, Hui Li, Andrew Connell, Michael P Hogarty, Kshitij Wagh, Shuyi Wang, Lorie Marchitto, Ashwin N. Skelly, John W Carey, Kirsten J. Sowers, Kasirajan Ayyanathan, Samantha J. Plante, Frédéric Bibollet‐Ruche, Younghoon Park, Colby J. Agostino, Ajay Singh, Christian L. Martella, Emily E. Lewis, Juliette Rando, Neha Chohan, Jinery Lora, Wenge Ding, Mary S Campion, Chengyan Zhao, Weimin Liu, Yong Li, Xuduo Li, Bo Liang, Rohan Roy Chowdhury, Khaled Amereh, Elizabeth Van Itallie, Zizhang Sheng, Amrit R Ghosh, Katharine J Bar, Wilton B. Williams, Kevin Wiehe, Kevin O. Saunders, Robert J Edwards, Derek W. Cain, Mark G Lewis, Facundo D Batista, Dennis R Burton, Raiees Andrabi, Daniel W. Kulp, Barton F Haynes, Bette Korber, Lawrence Shapiro, Peter D Kwong, Beatrice H. Hahn, George M Shaw
Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by 1 of 16 different simian-human immunodeficiency viruses (SHIVs). We identified the V2 apex region of the envelope (Env) as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is a primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as vaccine platforms.