Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers.
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.
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.
Claudia
C
Blattner
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.
Jeong Hyun
JH
Lee
Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
Kwinten
K
Sliepen
Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
Ronald
R
Derking
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.
Emilia
E
Falkowska
Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
Alba Torrents
AT
de la Peña
Weill Medical College of Cornell University, New York, NY 10021, USA.
Albert
A
Cupo
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.
Jean-Philippe
JP
Julien
Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
Marit
M
van Gils
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Peter S
PS
Lee
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.
Wenjie
W
Peng
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.
James C
JC
Paulson
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.
Pascal
P
Poignard
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.
Dennis R
DR
Burton
Weill Medical College of Cornell University, New York, NY 10021, USA.
John P
JP
Moore
Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands; Weill Medical College of Cornell University, New York, NY 10021, USA.
Rogier W
RW
Sanders
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: wilson@scripps.edu.
Ian A
IA
Wilson
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: abward@scripps.edu.
Andrew B
AB
Ward
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000648:ultrastructure; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000648:ultrastructure; D001666:Binding Sites, Antibody / Q000276:immunology; D002460:Cell Line; D003460:Crystallization; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology* / Q000648:ultrastructure; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000276:immunology; D020836:Protein Structure, Quaternary; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D011134:Polysaccharides; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1