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Cell. 2016 Sep 8;166(6):1471-1484.e18. doi: 10.1016/j.cell.2016.07.029.

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

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
2
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
3
Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
4
Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37232, USA.
5
Fred Hutchinson Cancer Research Center, Seattle, WA 02129, USA.
6
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
7
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Cambridge, MA 02129, USA; Harvard University, Cambridge, MA 02129, USA.
8
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
9
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
10
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Electronic address: jmascola@mail.nih.gov.
11
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: alt@enders.tch.harvard.edu.

Abstract

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.

PMID:
27610571
PMCID:
PMC5103708
DOI:
10.1016/j.cell.2016.07.029
[Indexed for MEDLINE]
Free PMC Article

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