Engineering B cells as an evolving drug to fight HIV

HIV viremia can be controlled by chronic antiretroviral therapy. As a potentially single-shot alternative, B cells engineered by CRISPR/Cas9 to express anti-HIV broadly neutralizing antibodies (bNAbs) were shown capable of secreting high antibody titers. Here, we demonstrate that, upon immunization, adoptively transferred engineered B cells home to germinal centers (GC) where they predominate over the endogenous response and differentiate to memory and plasma cells while undergoing class switch recombination (CSR). Immunization with a higher affinity antigen increases accumulation in GCs and CSR rates. Boost immunization increases GC B cell rates and antibody secretion, indicating memory retention. Finally, engineered B cells in GCs amass amino acid substitutions in patterns signifying somatic hypermutation followed by selection. B cells may thus be engineered as a living and evolving drug.