Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice

作者：Eleonora Melzi, Jordan R. Willis, Mark Krystal, Ying‐Cing Lin, Sven Kratochvil, Zachary T. Berndsen, Elise Landais, Kalyuzhniy Oleksandr, Usha Nair, John E. Warner, Jon M. Steichen, Anton Kalyuzhniy, Amber Le, Simone Pecetta, Manfredo Perez, Kathrin H. Kirsch, Stephanie R. Weldon, Samantha Falcone, Sunny Himansu, Andrea Carfı́, Devin Sok, Andrew B. Ward, William R. Schief, Facundo D. Batista · 发表于：Immunity · 年份：2022 · DOI：10.1016/j.immuni.2022.09.003 · 被引用次数：67 · 研究领域：HIV Research and Treatment、Immune Cell Function and Interaction、T-cell and B-cell Immunology

Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination targets. To evaluate Apex germline-targeting (ApexGT) vaccine candidates, we engineered knockin (KI) mouse models expressing the germline B cell receptor (BCR) of the bnAb PCT64. We found that high affinity of the ApexGT immunogen for PCT64-germline BCRs was necessary to specifically activate KI B cells at human physiological frequencies, recruit them to germinal centers, and select for mature bnAb mutations. Relative to protein, mRNA-encoded membrane-bound ApexGT immunization significantly increased activation and recruitment of PCT64 precursors to germinal centers and lowered their affinity threshold. We have thus developed additional models for HIV vaccine research, validated ApexGT immunogens for priming V2-apex bnAb precursors, and identified mRNA-LNP as a suitable approach to substantially improve the B cell response.