Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development
Habib R, Roark RS, Li H, Connell AJ, Hogarty MP, Wagh K, Wang S, Marchitto L, Skelly AN, Carey JW, Sowers KJ, Ayyanathan K, Plante SJ, Bibollet-Ruche F, Park Y, Agostino CJ, Singh A, Martella CL, Lewis E, Rando JM, Chohan N, Lora J, Ding W, Campion MS, Zhao C, Liu W, Li Y, Li X, Liang B, Chowdhury RR, Amereh K, Van Itallie E, Sheng Z, Ghosh AR, Bar KJ, Williams WB, Wiehe K, Saunders KO, Edwards RJ, Cain DW, Lewis M, Batista FD, Burton DR, Andrabi R, Kulp DW, Haynes BF, Korber B, Shapiro L, Kwong PD, Hahn BH, Shaw GM. Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development. bioRxiv [Preprint]. 2025 Sep 19:2025.05.03.652068. doi: 10.1101/2025.05.03.652068. PMID: 40502159; PMCID: PMC12154871.
Abstract
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 one of 16 different simian-human immunodeficiency viruses (SHIVs). We identified V2 apex 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 the primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as novel vaccine platforms.