Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

Till Schoofs; Christopher O Barnes; Nina Suh-Toma; Jovana Golijanin; Philipp Schommers; Henning Gruell; Anthony P West Jr; Franziska Bach; Yu Erica Lee; Lilian Nogueira; Ivelin S Georgiev; Robert T Bailer; Julie Czartoski; John R Mascola; Michael S Seaman; M Juliana McElrath; Nicole A Doria-Rose; Florian Klein; Michel C Nussenzweig; Pamela J Bjorkman

doi:10.1016/j.immuni.2019.04.014

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

Immunity. 2019 Jun 18;50(6):1513-1529.e9. doi: 10.1016/j.immuni.2019.04.014. Epub 2019 May 21.

Authors

Till Schoofs¹, Christopher O Barnes², Nina Suh-Toma³, Jovana Golijanin⁴, Philipp Schommers⁵, Henning Gruell⁵, Anthony P West Jr², Franziska Bach⁶, Yu Erica Lee², Lilian Nogueira⁴, Ivelin S Georgiev⁷, Robert T Bailer⁸, Julie Czartoski⁹, John R Mascola⁸, Michael S Seaman¹⁰, M Juliana McElrath⁹, Nicole A Doria-Rose⁸, Florian Klein¹¹, Michel C Nussenzweig¹², Pamela J Bjorkman¹³

Affiliations

¹ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, partner site Bonn-Cologne, 50931 Cologne, Germany.
² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Westridge High School, 324 Madeline Drive, Pasadena, CA 91105, USA.
⁴ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
⁵ Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, partner site Bonn-Cologne, 50931 Cologne, Germany.
⁶ Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany.
⁷ Vanderbilt Vaccine Center, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN 37232, USA.
⁸ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
¹⁰ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹¹ Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, partner site Bonn-Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
¹² Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: nussen@rockefeller.edu.
¹³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: bjorkman@caltech.edu.

Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448_gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

Keywords: Env trimer; HIV-1; HIV-1 Env silent face; HIV-1 vaccine; broadly neutralizing antibody; cryo-EM; glycan recognition; humanized mice; immunotherapy.

Publication types

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

MeSH terms

Amino Acid Sequence
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / isolation & purification
Antibody Affinity / immunology
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Epitopes / chemistry
Epitopes / immunology
Glycosylation
HIV Antibodies / immunology*
HIV Antibodies / isolation & purification
HIV Envelope Protein gp120 / chemistry
HIV Envelope Protein gp120 / immunology
HIV Infections / immunology*
HIV Infections / virology
HIV-1 / classification
HIV-1 / genetics
HIV-1 / immunology*
Humans
Models, Molecular
Phylogeny
Polysaccharides / chemistry
Polysaccharides / metabolism
Protein Binding / immunology
Protein Conformation
env Gene Products, Human Immunodeficiency Virus / chemistry
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / immunology*
env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

Antibodies, Neutralizing
Epitopes
HIV Antibodies
HIV Envelope Protein gp120
Polysaccharides
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding