Enhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies

Efficient priming of B cell precursors is a rate-limiting step in the induction of V2 apex broadly neutralizing antibodies (bnAbs)^1,2. Here we describe a germline-targeted HIV-1 Env (CAP256.OPT4) that increases the efficiency of V2 apex bnAb precursor priming by 30-400-fold compared with wild-type HIV-1 Envs and induces, in over 90% of macaques, neutralization breadth that includes Asn130-containing viruses. Using three different delivery platforms-persistently replicating simian human immunodeficiency viruses (SHIVs), protein nanoparticles and mRNA-we show bnAb priming as early as 4 weeks after infection or immunization, and neutralization breadth in the plasma by 12 weeks. In 14 SHIV-infected macaques, neutralization breadth reached as high as 90% on a 21-virus panel with potency as great as 1:20,000 (50% inhibitory dilution). Monoclonal bnAbs isolated from these animals were similarly broad and potent, with cryo-EM structures representing three distinct lineages revealing canonical needle-like HCDR3 binding. Env-Ab coevolution and structural analyses identified five key residues and loop features under positive selection and temporally associated with neutralization breadth. Importantly, prime-boost immunogens designed to capture these features induced broad and potent neutralization of globally diverse viruses including those containing Asn130 glycan. Furthermore, rhesus bnAbs were not restricted to IGHD3-15*01 heavy-chain alleles. These results expand the use of the rhesus model for HIV-1 vaccine design and provide a molecular blueprint for inducing V2 apex bnAbs in rhesus and humans.