Guiding the long way to broad HIV neutralization

It has been demonstrated that extensive virus diversification and antibody coevolution are necessary to give rise to broadly neutralizing antibodies targeting the envelope protein of HIV-1. Here, we discuss recent progress of vaccine design approaches aiming on strategies to initiate and guide B-cell development toward this outcome, as well as their evaluation in mouse models engineered to express human antibodies.

Several specially tailored transgenic mouse strains have been developed to test the concept of engaging and guiding B-cell development by sequential immunizations. Currently available models display prerearranged or nonrearranged germline or mature VDJH and VJL loci of CD4-binding-site-specific (VRC01, 3BNC60) and high-mannose-patch-specific (PGT121) broadly neutralizing antibodies, or even the complete human V(D)J segments. Data generated in these knock-in mouse models elegantly prove the feasibility of the concept when using a carefully selected panel of engineered envelope proteins.

Recent studies in knock-in transgenic mouse models provide a proof-of-concept that germline B-cell receptor targeting followed by sequential immunization can engage the respective naïve precursor B cells and guide B-cell receptor development toward broadly neutralizing reactivity.