B cell priming, rather than affinity maturation complexity, constitutes the primary bottleneck to V2 apex broadly neutralizing antibody elicitation during HIV-1 infection, as evidenced by the restriction of V2 apex bNAb development to specific germline-sensitive Envs, the rarity of required B cell precursor features in the naive repertoire, the rapid and permissive maturation pathways driven by limited C-strand mutations once priming occurs, and the absence of C-strand viral escape in animals lacking V2 apex bNAbs indicating failed priming rather than failed maturation.

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.

B cell priming is the primary bottleneck to HIV-1 V2 apex bNAb elicitation.