title: Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice.
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.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Dosenovic
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Lotta
authors.initials: L
authors.lastname: von Boehmer
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Escolano
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jardine
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Natalia T
authors.initials: NT
authors.lastname: Freund
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Gitlin
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McGuire
authors.affiliation: 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.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kulp
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Thiago
authors.initials: T
authors.lastname: Oliveira
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Scharf
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Gray
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Cupo
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Marit J
authors.initials: MJ
authors.lastname: van Gils
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Kai-Hui
authors.initials: KH
authors.lastname: Yao
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Cassie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Howard Hughes Medical Institute; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Björkman
authors.affiliation: 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.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.affiliation: 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.
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute. Electronic address: nussen@rockefeller.edu.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000235:genetics*; D000914:Antibodies, Viral / Q000235:genetics*; D000956:Antigens, Viral; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D055879:Gene Knock-In Techniques; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D009154:Mutation; D013154:Spleen / Q000166:cytology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D015704:CD4 Antigens; D007143:Immunoglobulin Heavy Chains; D054299:env Gene Products, Human Immunodeficiency Virus