A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure

Jeong Hyun Lee; Raiees Andrabi; Ching-Yao Su; Anila Yasmeen; Jean-Philippe Julien; Leopold Kong; Nicholas C Wu; Ryan McBride; Devin Sok; Matthias Pauthner; Christopher A Cottrell; Travis Nieusma; Claudia Blattner; James C Paulson; Per Johan Klasse; Ian A Wilson; Dennis R Burton; Andrew B Ward

doi:10.1016/j.immuni.2017.03.017

A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure

Immunity. 2017 Apr 18;46(4):690-702. doi: 10.1016/j.immuni.2017.03.017.

Authors

Jeong Hyun Lee¹, Raiees Andrabi², Ching-Yao Su³, Anila Yasmeen⁴, Jean-Philippe Julien⁵, Leopold Kong⁶, Nicholas C Wu⁶, Ryan McBride⁷, Devin Sok², Matthias Pauthner², Christopher A Cottrell¹, Travis Nieusma⁶, Claudia Blattner¹, James C Paulson⁷, Per Johan Klasse⁴, Ian A Wilson⁸, Dennis R Burton⁹, Andrew B Ward¹⁰

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Weill Medical College of Cornell University, New York, New York 10065, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Program in Molecular Structure and Function, Hospital for Sick Children Research Institute, and Departments of Biochemistry and Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
⁶ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁷ Department of Cell and Molecular Biology and Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
⁸ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁹ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, MIT and Harvard, Boston, MA 02139, USA. Electronic address: burton@scripps.edu.
¹⁰ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: andrew@scripps.edu.

Abstract

Broadly neutralizing antibodies (bnAbs) to HIV delineate vaccine targets and are prophylactic and therapeutic agents. Some of the most potent bnAbs target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer. Using cryo-electron microscopy, we solved the atomic structure of an apex bnAb, PGT145, in complex with Env. We showed that the long anionic HCDR3 of PGT145 penetrated between glycans at the trimer 3-fold axis, to contact peptide residues from all three Env protomers, and thus explains its highly trimer-specific nature. Somatic hypermutation in the other CDRs of PGT145 were crucially involved in stabilizing the structure of the HCDR3, similar to bovine antibodies, to aid in recognition of a cluster of conserved basic residues hypothesized to facilitate trimer disassembly during viral entry. Overall, the findings exemplify the creative solutions that the human immune system can evolve to recognize a conserved motif buried under a canopy of glycans.

Keywords: HIV; PGT145; broadly neutralizing antibody; cryo-electron microscopy; envelope glycoprotein; trimer apex.

Publication types

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

MeSH terms

Amino Acid Sequence
Anions / chemistry
Antibodies, Neutralizing / chemistry*
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / metabolism
Cryoelectron Microscopy
Crystallography, X-Ray
Epitopes / chemistry
Epitopes / immunology
Epitopes / metabolism
HEK293 Cells
HIV Antibodies / chemistry
HIV Antibodies / immunology
HIV Antibodies / metabolism
HIV-1 / immunology
HIV-1 / metabolism
Humans
Models, Molecular
Polysaccharides / chemistry
Polysaccharides / immunology
Polysaccharides / metabolism
Protein Binding / immunology
Protein Domains*
Protein Multimerization*
Protein Structure, Secondary*
Sequence Homology, Amino Acid
Surface Plasmon Resonance
env Gene Products, Human Immunodeficiency Virus / chemistry*
env Gene Products, Human Immunodeficiency Virus / immunology
env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

Anions
Antibodies, Neutralizing
Epitopes
HIV Antibodies
Polysaccharides
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding