B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models.

Animal models of human antigen-specific B cell receptors (BCRs) generally depend on "inferred germline" sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three BCR knockin mice. The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18

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Copyright © 2020 the Author(s). Published by PNAS.

Déclaration de conflit d'intérêts

Competing interest statement: W.R.S. is an inventor on a patent application submitted by IAVI and The Scripps Research Institute that covers the eOD-GT8 immunogen. W.R.S. is involved as a principal investigator of a human clinical trial involving eOD-GT8 60mer (G001). As part of that involvement, W.R.S. is privy to certain clinical trial data, and he was forbidden from sharing that data with the authors of this study during the course of this HuGL study, as is standard for blinded clinical trials. Any conclusions in this manuscript regarding relationships between HuGL mouse models and humans were made by the other authors, without input from W.R.S. related to any clinical trial activities.