B cells from knock-in mouse expressing broadly neutralizing HIV antibody b12 carry an innocuous BCR responsive to HIV vaccine candidates

• Published in: The Journal of immunology (1950) 2013-08, Vol.191 (6), p.3179-3185
• Main Authors: Ota, Takayuki, Doyle-Cooper, Colleen, Cooper, Anthony B., Doores, Katherine J., Aoki-Ota, Miyo, Le, Khoa, Schief, William R., Wyatt, Richard T., Burton, Dennis R., Nemazee, David
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1301283

Broadly neutralizing antibodies (bNAbs) against HIV protect from infection, but their routine elicitation by vaccination has not been achieved. To generate small animal models to test vaccine candidates, we have generated targeted transgenic (“knock-in”) mice expressing, in the physiological immunoglobulin heavy (H) and light (L) chain loci, two well-studied bNAbs: 4E10, which interacts with the membrane proximal external region of gp41, and b12, which binds to the CD4 binding site on gp120. 4E10HL mice are described in the accompanying paper. Here, we describe b12 mice. B cells in b12HL mice, in contrast to the case in 4E10 mice, were abundant and essentially monoclonal, retaining the b12 specificity. In cell culture, b12HL B cells responded avidly to HIV Env gp140 trimers and to BCR ligands, but only weakly to HIV pseudovirions. Upon transfer to wild type recipients, b12HL B cells responded robustly to vaccination with gp140 trimers. Vaccinated b12H mice, while generating abundant precursors and antibodies with affinity for Env, were unable to rapidly generate neutralizing antibodies, highlighting the importance of developing antigen forms that better focus responses to neutralizing epitopes. b12HL and b12H mice should be useful in optimizing HIV vaccine candidates to elicit a neutralizing response while avoiding non-protective specificities.