Targeted Selection of HIV-Specific Antibody Mutations by Engineering B Cell Maturation

Abstract

Engineering the immune system by design of immunogens to direct antibody maturation is a major goal of vaccinologists. One of the roadblocks preventing HIV vaccine development is the requirement for broadly neutralizing antibodies (bnAbs) to acquire somatic mutations rarely made by activation-induced cytidine deaminase. Here, we designed immunogens that bind with higher affinity to antibodies with improbable mutations than to unmutated precursor antibodies. We demonstrated for two bnAb B cell lineages using knockin mouse models that such immunogens engaged unmutated bnAb precursors, selected for functional improbable mutations, and induced neutralizing antibodies. Structural studies revealed how bnAb precursors interacted with Env and revealed the functions of the elicited improbable mutations. In primates, the CD4 binding site-targeting immunogen induced potent CD4 binding site neutralizing antibodies in macaques. This immunogen design strategy will allow for the delineation of sequential immunogens to direct bnAb development for HIV-1 and other pathogens.