Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model
Author:
Musharrafieh Rami, Safonova Yana, Song Ge, Roark Ryan S., Lee Fang-Hua, Zhang Shiyu, Hurtado Jonathan, Yong Peter, Wang Shuyi, Russell Ronnie M., Ding Wenge, Li Yingying, Rando Juliette, Murphy Alexander I., Lindemuth Emily, Zhao Chengyan, Connell Andrew Jesse, Lee Wen-Hsin, Mishra Nitesh, Avillion Gabriel, He Wanting, Callaghan Sean, Dueker Katharina, Vo Anh L., Li Xuduo, Capozzola Tazio, Joyce CollinORCID, Zhao FangzhuORCID, Anzanello Fabio, Liu Weimin, Bibollet-Ruche Frederic, Ramos Alejandra, Li Hui, Lewis Mark G., Ozorowski Gabriel, Landais Elise, Foley Brian T., Wagh Kshitij, Sok Devin, Briney Bryan, Ward Andrew B.ORCID, Hahn Beatrice H., Burton Dennis R., Shaw George M., Andrabi Raiees
Abstract
SUMMARYEliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation.Graphical Abstract
Publisher
Cold Spring Harbor Laboratory
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