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

Ming Tian; Cheng Cheng; Xuejun Chen; Hongying Duan; Hwei-Ling Cheng; Mai Dao; Zizhang Sheng; Michael Kimble; Lingshu Wang; Sherry Lin; Stephen D Schmidt; Zhou Du; M Gordon Joyce; Yiwei Chen; Brandon J DeKosky; Yimin Chen; Erica Normandin; Elizabeth Cantor; Rita E Chen; Nicole A Doria-Rose; Yi Zhang; Wei Shi; Wing-Pui Kong; Misook Choe; Amy R Henry; Farida Laboune; Ivelin S Georgiev; Pei-Yi Huang; Suvi Jain; Andrew T McGuire; Eric Georgeson; Sergey Menis; Daniel C Douek; William R Schief; Leonidas Stamatatos; Peter D Kwong; Lawrence Shapiro; Barton F Haynes; John R Mascola; Frederick W Alt

doi:10.1016/j.cell.2016.07.029

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

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

Authors

Ming Tian¹, Cheng Cheng², Xuejun Chen², Hongying Duan², Hwei-Ling Cheng¹, Mai Dao¹, Zizhang Sheng³, Michael Kimble¹, Lingshu Wang², Sherry Lin¹, Stephen D Schmidt², Zhou Du¹, M Gordon Joyce², Yiwei Chen¹, Brandon J DeKosky², Yimin Chen¹, Erica Normandin², Elizabeth Cantor¹, Rita E Chen², Nicole A Doria-Rose², Yi Zhang², Wei Shi², Wing-Pui Kong², Misook Choe², Amy R Henry², Farida Laboune², Ivelin S Georgiev⁴, Pei-Yi Huang¹, Suvi Jain¹, Andrew T McGuire⁵, Eric Georgeson⁶, Sergey Menis⁶, Daniel C Douek², William R Schief⁷, Leonidas Stamatatos⁵, Peter D Kwong², Lawrence Shapiro⁸, Barton F Haynes⁹, John R Mascola¹⁰, Frederick W Alt¹¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Broadly Neutralizing Antibodies
HIV Antibodies
Immunoglobulin Heavy Chains
VRC01 monoclonal antibody

Abstract

Publication types

MeSH terms

Substances

Grants and funding