Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

A substantial fraction of broadly neutralizing antibodies (bnAbs) in certain HIV-infected donors recognizes glycan-dependent epitopes on HIV-1 gp120. Here, we elucidate how bnAb PGT 135 recognizes its Asn332 glycan-dependent epitope from its crystal structure with gp120, CD4 and Fab 17b at 3.1 Å resolution. PGT 135 interacts with glycans at Asn332, Asn392 and Asn386, using long CDR loops H1 and H3 to penetrate the glycan shield to access the gp120 protein surface. Electron microscopy reveals PGT 135 can accommodate the conformational and chemical diversity of gp120 glycans by altering its angle of engagement. The combined structural studies of PGT 135, PGT 128 and 2G12 show this Asn332-dependent epitope is highly accessible and much more extensive than initially appreciated, allowing for multiple binding modes and varied angles of approach, thereby representing a supersite of vulnerability for antibody neutralization.

Related collections

Most cited references 26

Record: found
Abstract: found
Article: not found

Molecular architecture of native HIV-1 gp120 trimers.

Jun Liu, Alberto Bartesaghi, Mario J. Borgnia … (2008)

The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.

0 comments Cited 257 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Tongqing Zhou, Ling Xu, Barna Dey … (2007)

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1. Supplementary information The online version of this article (doi:10.1038/nature05580) contains supplementary material, which is available to authorized users.

0 comments Cited 224 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Antibody domain exchange is an immunological solution to carbohydrate cluster recognition.

Daniel A Calarese, Christopher Scanlan, Michael B. Zwick … (2003)

Human antibody 2G12 neutralizes a broad range of human immunodeficiency virus type 1 (HIV-1) isolates by binding an unusually dense cluster of carbohydrate moieties on the "silent" face of the gp120 envelope glycoprotein. Crystal structures of Fab 2G12 and its complexes with the disaccharide Manalpha1-2Man and with the oligosaccharide Man9GlcNAc2 revealed that two Fabs assemble into an interlocked VH domain-swapped dimer. Further biochemical, biophysical, and mutagenesis data strongly support a Fab-dimerized antibody as the prevalent form that recognizes gp120. The extraordinary configuration of this antibody provides an extended surface, with newly described binding sites, for multivalent interaction with a conserved cluster of oligomannose type sugars on the surface of gp120. The unique interdigitation of Fab domains within an antibody uncovers a previously unappreciated mechanism for high-affinity recognition of carbohydrate or other repeating epitopes on cell or microbial surfaces.

0 comments Cited 163 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 101186374

Journal ID (pubmed-jr-id): 31761

Journal ID (nlm-ta): Nat Struct Mol Biol

Journal ID (iso-abbrev): Nat. Struct. Mol. Biol.

Title: Nature structural & molecular biology

ISSN (Print): 1545-9993

ISSN (Electronic): 1545-9985

Publication date Nihms-submitted: 24 October 2013

Publication date (Electronic): 26 May 2013

Publication date (Print): July 2013

Publication date PMC-release: 01 January 2014

Volume: 20

Issue: 7

Electronic Location Identifier: 10.1038/nsmb.2594

Affiliations

[1 ]Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA

[2 ]International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA

[3 ]Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

[4 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA

[5 ]Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA

[6 ]Glycosciences Laboratory, Department of Medicine, Imperial College London, London, UK

[7 ]Weill Medical College of Cornell University, New York, New York, USA

[8 ]International AIDS Vaccine Initiative Design and Development Laboratory, Brooklyn, New York, USA

[9 ]Joint Center for Structural Genomics, http://www.jcsg.org, USA

[11 ]Department of Medical Microbiology, Academic Medical Center, Amsterdam, Netherlands

[12 ]Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA

[13 ]Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

Author notes

Correspondence should be addressed to D. R. B ( burton@ 123456scripps.edu ), A.B.W. ( abward@ 123456scripps.edu ) or I.A.W. ( wilson@ 123456scripps.edu )

Article

Manuscript ID: NIHMS464890

DOI: 10.1038/nsmb.2594

PMC ID: 3823233

PubMed ID: 23708606

SO-VID: 2456aaa5-6ec0-4c70-b176-b09471db8f03

License:

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

History

Funding

Funded by: National Institute of General Medical Sciences : NIGMS

Award ID: R01 GM046192 || GM

Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID

Award ID: R01 AI084817 || AI

Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID

Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120

Read this article at

Abstract

Related collections

Higher order chromatin architecture

Most cited references 26

Molecular architecture of native HIV-1 gp120 trimers.

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Antibody domain exchange is an immunological solution to carbohydrate cluster recognition.

Author and article information

Journal

Affiliations

Author notes

Article

History

Funding

Categories

Comments

Comment on this article

Similar content 270

Cited by 135

Most referenced authors 2,115