Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires

The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive fro...

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Bibliographic Details
Published in:	Cell Vol. 166; no. 6; pp. 1471 - 1484.e18
Main Authors:	Tian, Ming, Cheng, Cheng, Chen, Xuejun, Duan, Hongying, Cheng, Hwei-Ling, Dao, Mai, Sheng, Zizhang, Kimble, Michael, Wang, Lingshu, Lin, Sherry, Schmidt, Stephen D., Du, Zhou, Joyce, M. Gordon, Chen, Yiwei, DeKosky, Brandon J., Chen, Yimin, Normandin, Erica, Cantor, Elizabeth, Chen, Rita E., Doria-Rose, Nicole A., Zhang, Yi, Shi, Wei, Kong, Wing-Pui, Choe, Misook, Henry, Amy R., Laboune, Farida, Georgiev, Ivelin S., Huang, Pei-Yi, Jain, Suvi, McGuire, Andrew T., Georgeson, Eric, Menis, Sergey, Douek, Daniel C., Schief, William R., Stamatatos, Leonidas, Kwong, Peter D., Shapiro, Lawrence, Haynes, Barton F., Mascola, John R., Alt, Frederick W.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 08-09-2016
Subjects:	Animals Antibodies, Monoclonal - genetics Antibodies, Monoclonal - immunology Antibodies, Neutralizing - immunology B-Lymphocytes - immunology Broadly Neutralizing Antibodies Cell Line Disease Models, Animal Gene Expression Regulation - immunology HIV Antibodies HIV-1 - immunology Immunization Immunoglobulin Heavy Chains - chemistry Immunoglobulin Heavy Chains - genetics Immunoglobulin Heavy Chains - immunology Inhibitory Concentration 50 Mice Precursor Cells, B-Lymphoid - immunology Sequence Deletion T-Lymphocytes - immunology
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Summary:	The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2∗02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2∗02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages. [Display omitted] •Mice generate diverse primary B cell receptors from a single human VH segment•An efficient new method generated mouse models for assessing human vaccination strategies•Step-wise immunization induced affinity maturation of HIV-neutralizing antibodies in mice Sequential immunization using modified HIV envelope glycoproteins supports the maturation of HIV-neutralizing antibody lineages in mouse models that have diverse antibody repertoire and therefore are closer to physiological immunization settings than conventional transgenic models.
Bibliography:	Lead Contact: Frederick W. Alt Equal Contribution
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2016.07.029