Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers

Claudia Blattner; Jeong Hyun Lee; Kwinten Sliepen; Ronald Derking; Emilia Falkowska; Alba Torrents de la Peña; Albert Cupo; Jean-Philippe Julien; Marit van Gils; Peter S Lee; Wenjie Peng; James C Paulson; Pascal Poignard; Dennis R Burton; John P Moore; Rogier W Sanders; Ian A Wilson; Andrew B Ward

doi:10.1016/j.immuni.2014.04.008

Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers

Immunity. 2014 May 15;40(5):669-80. doi: 10.1016/j.immuni.2014.04.008. Epub 2014 Apr 24.

Authors

Claudia Blattner¹, Jeong Hyun Lee², Kwinten Sliepen³, Ronald Derking³, Emilia Falkowska⁴, Alba Torrents de la Peña³, Albert Cupo⁵, Jean-Philippe Julien², Marit van Gils³, Peter S Lee⁶, Wenjie Peng⁷, James C Paulson⁷, Pascal Poignard⁴, Dennis R Burton⁸, John P Moore⁵, Rogier W Sanders⁹, Ian A Wilson¹⁰, Andrew B Ward¹¹

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Integrative Structural and Computational Biology, 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 Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁴ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Weill Medical College of Cornell University, New York, NY 10021, USA.
⁶ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁷ Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ 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; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02129, USA.
⁹ Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands; Weill Medical College of Cornell University, New York, NY 10021, USA.
¹⁰ Department of Integrative Structural and Computational Biology, 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; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
¹¹ Department of Integrative Structural and Computational Biology, 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. Electronic address: [email protected].

Abstract

All previously characterized broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) target one of four major sites of vulnerability. Here, we define and structurally characterize a unique epitope on Env that is recognized by a recently discovered family of human monoclonal antibodies (PGT151-PGT158). The PGT151 epitope is comprised of residues and glycans at the interface of gp41 and gp120 within a single protomer and glycans from both subunits of a second protomer and represents a neutralizing epitope that is dependent on both gp120 and gp41. Because PGT151 binds only to properly formed, cleaved trimers, this distinctive property, and its ability to stabilize Env trimers, has enabled the successful purification of mature, cleaved Env trimers from the cell surface as a complex with PGT151. Here we compare the structural and functional properties of membrane-extracted Env trimers from several clades with those of the soluble, cleaved SOSIP gp140 trimer.

Publication types

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

MeSH terms

Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / ultrastructure
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / ultrastructure
Binding Sites, Antibody / immunology
Cell Line
Crystallization
Crystallography, X-Ray
Epitopes / immunology
HEK293 Cells
HIV Antibodies / immunology*
HIV Antibodies / ultrastructure
HIV Envelope Protein gp120 / immunology*
HIV Envelope Protein gp41 / immunology*
HIV Envelope Protein gp41 / metabolism
HIV Infections / immunology
HIV Infections / prevention & control
HIV-1 / immunology
Humans
Molecular Sequence Data
Polysaccharides / immunology
Protein Structure, Quaternary
env Gene Products, Human Immunodeficiency Virus / immunology

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Epitopes
HIV Antibodies
HIV Envelope Protein gp120
HIV Envelope Protein gp41
Polysaccharides
env Gene Products, Human Immunodeficiency Virus
gp140 envelope protein, Human immunodeficiency virus 1
gp41 protein, Human immunodeficiency virus 1

Associated data

PDB/4NUG
PDB/4NUJ

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding