Enhanced B cell priming induces broadly neutralizing HIV-1 apex antibodies.
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Marchitto Lorie, Wagh Kshitij, Roark Ryan S, Coleon Severin, Li Hui, Skelly Ashwin N, Hogarty Michael P, Habib Rumi, Ding Wenge, Ayyanathan Kasirajan, Liu Weimin, Sheng Zizhang, Guo Yicheng, Bal Joena, Smith Lena M, Sutherland Laura L, Park Younghoon, Connell Andrew J, Bibollet-Ruche Frederic, Lewis Emily, Plante Samantha J, Akeley Macy J, Lora Jinery, Zhao Chengyan, Carey John W, Martella Christian L, Li Yingying, Campion Mary S, Lituchy Melinda G, Osbaldeston Rebecca A, Gordon Colette G, Albertus Amie, Su Justin, Noguchi Chiaki, Tam Ying K, Barbosa Christopher, Liang Bo, Amereh Khaled, Li Xuduo, Walsh Agnes A, Irvine Darrell J, Andrabi Raiees, Edwards Robert J, Kreider Edward F, Weissman Drew, Shapiro Lawrence, Kwong Peter D, Korber Bette T, Haynes Barton F, Saunders Kevin O, Hahn Beatrice H, Shaw George M
Аннотация
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.