B cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates.

TitleB cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates.
Publication TypeJournal Article
Year of Publication2013
AuthorsOta T, Doyle-Cooper C, Cooper AB, Doores KJ, Aoki-Ota M, Le K, Schief WR, Wyatt RT, Burton DR, Nemazee D
JournalJ Immunol
Volume191
Issue6
Pagination3179-85
Date Published09/15/2013
ISSN1550-6606
KeywordsAIDS Vaccines, Animals, Antibodies, Neutralizing, B-Lymphocytes, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Knock-In Techniques, HIV Antibodies, HIV Antigens, HIV Envelope Protein gp120, HIV Envelope Protein gp41, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Antigen, B-Cell
Abstract

Broadly neutralizing Abs 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 Ig H and L chain loci, two well-studied broadly neutralizing Abs: 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 companion article (Doyle-Cooper et al., J. Immunol. 191: 3186-3191). In this article, 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 envelope gp140 trimers and to BCR ligands. Upon transfer to wild-type recipients, b12HL B cells responded robustly to vaccination with gp140 trimers. Vaccinated b12H mice, although generating abundant precursors and Abs with affinity for Env, were unable to rapidly generate neutralizing Abs, highlighting the importance of developing Ag forms that better focus responses to neutralizing epitopes. The b12HL and b12H mice should be useful in optimizing HIV vaccine candidates to elicit a neutralizing response while avoiding nonprotective specificities.

DOI10.4049/jimmunol.1301283
Alternate JournalJ. Immunol.
PubMed ID23940273
PubMed Central IDPMC3773231
Grant ListR01 AI059714 / AI / NIAID NIH HHS / United States
R01 AI073148 / AI / NIAID NIH HHS / United States
R01AI073148 / AI / NIAID NIH HHS / United States
R56 AI073148 / AI / NIAID NIH HHS / United States
U01AI078224 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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