Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice

Pia Dosenovic; Lotta von Boehmer; Amelia Escolano; Joseph Jardine; Natalia T Freund; Alexander D Gitlin; Andrew T McGuire; Daniel W Kulp; Thiago Oliveira; Louise Scharf; John Pietzsch; Matthew D Gray; Albert Cupo; Marit J van Gils; Kai-Hui Yao; Cassie Liu; Anna Gazumyan; Michael S Seaman; Pamela J Björkman; Rogier W Sanders; John P Moore; Leonidas Stamatatos; William R Schief; Michel C Nussenzweig

doi:10.1016/j.cell.2015.06.003

Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice

Cell. 2015 Jun 18;161(7):1505-15. doi: 10.1016/j.cell.2015.06.003.

Authors

Pia Dosenovic¹, Lotta von Boehmer¹, Amelia Escolano¹, Joseph Jardine², Natalia T Freund¹, Alexander D Gitlin¹, Andrew T McGuire³, Daniel W Kulp², Thiago Oliveira¹, Louise Scharf⁴, John Pietzsch¹, Matthew D Gray³, Albert Cupo⁵, Marit J van Gils⁶, Kai-Hui Yao¹, Cassie Liu¹, Anna Gazumyan⁷, Michael S Seaman⁸, Pamela J Björkman⁹, Rogier W Sanders¹⁰, John P Moore⁵, Leonidas Stamatatos¹¹, William R Schief¹², Michel C Nussenzweig¹³

Affiliations

¹ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
² Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁵ Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, NY 10065, USA.
⁶ Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
⁷ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute.
⁸ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁹ Howard Hughes Medical Institute; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁰ Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, NY 10065, USA; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
¹¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98109, USA.
¹² Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02129, USA. Electronic address: schief@scripps.edu.
¹³ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute. Electronic address: nussen@rockefeller.edu.

Abstract

A subset of individuals infected with HIV-1 develops broadly neutralizing antibodies (bNAbs) that can prevent infection, but it has not yet been possible to elicit these antibodies by immunization. To systematically explore how immunization might be tailored to produce them, we generated mice expressing the predicted germline or mature heavy chains of a potent bNAb to the CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein (Env). Immunogens specifically designed to activate B cells bearing germline antibodies are required to initiate immune responses, but they do not elicit bNAbs. In contrast, native-like Env trimers fail to activate B cells expressing germline antibodies but elicit bNAbs by selecting for a restricted group of light chains bearing specific somatic mutations that enhance neutralizing activity. The data suggest that vaccination to elicit anti-HIV-1 antibodies will require immunization with a succession of related immunogens.

Publication types

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

MeSH terms

Animals
Antibodies, Neutralizing / genetics*
Antibodies, Viral / genetics*
Antigens, Viral
B-Lymphocytes / immunology
CD4 Antigens / metabolism
Gene Knock-In Techniques*
HIV Infections / immunology
HIV-1 / immunology*
Humans
Immunoglobulin Heavy Chains / genetics*
Mice
Mutation
Spleen / cytology
env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

Antibodies, Neutralizing
Antibodies, Viral
Antigens, Viral
CD4 Antigens
Immunoglobulin Heavy Chains
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding