Humanized Mouse with a Diverse Polyclonal B Cell Repertoire as a Model for Neutralizing Antibody Responses against EBV and HIV

Abstract

Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) cause diseases of global health importance. However, it has been historically difficult to model human neutralizing B cell responses to these two viruses using small animals. I leveraged a transgenic mouse model that encodes a genetically human antibody repertoire to generate neutralizing monoclonal antibodies (mAbs) against the EBV gp350 and gp42 glycoproteins, which have been technically difficult to isolate from natural infection. gp42 and gp350 are involved in attachment and fusion into B cells respectively. Thus, these mAbs have great potential as therapeutic agents against EBV-associated malignancies. In a second project, I investigated the utility of these humanized mice as a surrogate to model VRC01-class B cell responses, a rare class of HIV broadly neutralizing antibodies that target the CD4 binding site on HIV envelope. I utilized high-throughput sequencing to identify the presence of these rare potentially protective B cells in humanized mice and evaluated if an anti-idiotypic immunogen, designed to target genetically encoded features of VRC01-class B cells, could selectively target and expand these cells in vivo.