in vivo modeling of IgH-reprogrammed B cells in mice

SUMMARY Durable HIV broadly neutralizing antibody (bnAb) serum titers can be elicited in mice from peripheral B cells that have been reprogrammed using CRISPR-cas to express such antibodies as functional antigen receptors (BCRs) from the IgH-locus. Since HIV bnAbs are capable of suppressing viremia in people living with HIV (PLWH), IgH- reprogrammed B cells are a promising approach to achieve an HIV functional cure. We have developed a robust mouse model that generates boostable ‘VRC01’ memory responses and serum titers approaching durable, effective antiviral concentrations after a sincle boost. We will use this model as a starting point to characterize and improve the function of engineered cells and vaccination prarmeters. This will be accomplished using optimized and well established tools, assays, and analytical pipelines specific for this model. We will then expand the model to include elicitation of memory responses from cells engineered to express other bnAbs that have been selected for eventual clinical development. Immunogens that elicit similar durable memory responses from these cells will be identified and this memory will be evaluated for its ability to respond to rare bnAb ‘escape variant’ antigens. Finally, next-generation IgH-reprogramming and in vivo delivery approaches will be evaluated in the mouse model. Advances in the mouse model that improve ex vivo or in vivo IgH-reprogramming of B cells and elicitation of durable bnAb responses from these cells is critical for the eventual design of experiments in NHPs and eventually, for the clinic.