Home LiteratureArticle Details
PMID: 21076402 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies.

Nature structural & molecular biology ·Vol. 17 ·No. 12 ·2010-12-00 ·Pages 1486-91

Frey G, Chen J, Rits-Volloch S, Freeman MM, Zolla-Pazner S, Chen B

Abstract

HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, adopting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting gp41's membrane-proximal external region in a fusion-intermediate state. Here we report biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, recognize a gp41 conformation that exists only when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1-infected individuals by gp41 in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design.

MeSH Terms
Antibodies, Monoclonal/chemistry,physiology Antibodies, Neutralizing/chemistry,immunology Antibodies, Viral/chemistry,immunology Crystallography, X-Ray HIV Envelope Protein gp41/chemistry,immunology HIV-1/immunology Humans Immunity, Humoral Immunoglobulin Fab Fragments/chemistry,physiology Models, Molecular Protein Structure, Tertiary Virus Internalization
Chemicals
Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral HIV Envelope Protein gp41 Immunoglobulin Fab Fragments gp41 protein, Human immunodeficiency virus 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Frey Gary
Division of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Chen Jia
Rits-Volloch Sophia
Freeman Michael M
Zolla-Pazner Susan
Chen Bing
References (58)
58 references, click to expand
  1. Oligomer-specific conformations of the human immunodeficiency virus (HIV-1) gp41 envelope glycoprotein ectodomain recognized by human monoclonal antibodies.
    AIDS Res Hum Retroviruses. 2009 Mar;25(3):319-28 PMID: 19292593
  2. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.
    Science. 2009 Oct 9;326(5950):285-9 PMID: 19729618
  3. Nature of nonfunctional envelope proteins on the surface of human immunodeficiency virus type 1.
    J Virol. 2006 Mar;80(5):2515-28 PMID: 16474158
  4. An affinity-enhanced neutralizing antibody against the membrane-proximal external region of human immunodeficiency virus type 1 gp41 recognizes an epitope between those of 2F5 and 4E10.
    J Virol. 2007 Apr;81(8):4033-43 PMID: 17287272
  5. Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine?
    Nat Med. 2009 Aug;15(8):866-70 PMID: 19525964
  6. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand.
    J Infect Dis. 2006 Dec 15;194(12):1661-71 PMID: 17109337
  7. Anti-V3 monoclonal antibodies display broad neutralizing activities against multiple HIV-1 subtypes.
    PLoS One. 2010 Apr 21;5(4):e10254 PMID: 20421997
  8. Phaser crystallographic software.
    J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674 PMID: 19461840
  9. Functional activities of 20 human immunodeficiency virus type 1 (HIV-1)-specific human monoclonal antibodies.
    AIDS Res Hum Retroviruses. 1995 Sep;11(9):1095-9 PMID: 8554906
  10. Molecular replacement with MOLREP.
    Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5 PMID: 20057045
  11. The crystal structure of the SIV gp41 ectodomain at 1.47 A resolution.
    J Struct Biol. 1999 Jun 15;126(2):131-44 PMID: 10388624
  12. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody.
    Science. 1994 Nov 11;266(5187):1024-7 PMID: 7973652
  13. Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design.
    Nat Rev Immunol. 2010 Jul;10(7):527-35 PMID: 20577269
  14. Characterization of gp41 as the transmembrane protein coded by the HTLV-III/LAV envelope gene.
    Science. 1985 Sep 27;229(4720):1402-5 PMID: 2994223
  15. Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41.
    J Cell Biol. 1998 Jan 26;140(2):315-23 PMID: 9442107
  16. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1.
    J Virol. 1996 Feb;70(2):1100-8 PMID: 8551569
  17. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1.
    J Virol. 1993 Nov;67(11):6642-7 PMID: 7692082
  18. Crystal structure of an isoleucine-zipper trimer.
    Nature. 1994 Sep 1;371(6492):80-3 PMID: 8072533
  19. Rapid evolution of the neutralizing antibody response to HIV type 1 infection.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4144-9 PMID: 12644702
  20. Neutralization of HIV-1 primary isolates by polyclonal and monoclonal human antibodies.
    Int Immunol. 1997 Sep;9(9):1281-90 PMID: 9310831
  21. Identification of sites within gp41 that serve as targets for antibody-dependent cellular cytotoxicity by using human monoclonal antibodies.
    J Immunol. 1990 Nov 15;145(10):3276-82 PMID: 1700004
  22. Nonneutralizing antibodies are able to inhibit human immunodeficiency virus type 1 replication in macrophages and immature dendritic cells.
    J Virol. 2006 Jun;80(12):6177-81 PMID: 16731957
  23. Effects of oligomerization on the epitopes of the human immunodeficiency virus type 1 envelope glycoproteins.
    Virology. 2000 Feb 15;267(2):220-8 PMID: 10662617
  24. Major glycoprotein antigens that induce antibodies in AIDS patients are encoded by HTLV-III.
    Science. 1985 May 31;228(4703):1091-4 PMID: 2986290
  25. Oligomeric structure of gp41, the transmembrane protein of human immunodeficiency virus type 1.
    J Virol. 1989 Jun;63(6):2674-9 PMID: 2786089
  26. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.
    Nature. 2002 Dec 12;420(6916):678-82 PMID: 12478295
  27. Refinement of macromolecular structures by the maximum-likelihood method.
    Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55 PMID: 15299926
  28. A potent cross-clade neutralizing human monoclonal antibody against a novel epitope on gp41 of human immunodeficiency virus type 1.
    AIDS Res Hum Retroviruses. 2001 Dec 10;17(18):1757-65 PMID: 11788027
  29. Epitope mapping of two immunodominant domains of gp41, the transmembrane protein of human immunodeficiency virus type 1, using ten human monoclonal antibodies.
    J Virol. 1991 Sep;65(9):4832-8 PMID: 1714520
  30. Recognition by human monoclonal antibodies of free and complexed peptides representing the prefusogenic and fusogenic forms of human immunodeficiency virus type 1 gp41.
    J Virol. 2000 Jul;74(13):6186-92 PMID: 10846104
  31. Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41.
    J Virol. 2001 Nov;75(22):10892-905 PMID: 11602729
  32. Three-dimensional solution structure of the 44 kDa ectodomain of SIV gp41.
    EMBO J. 1998 Aug 17;17(16):4572-84 PMID: 9707417
  33. Core structure of gp41 from the HIV envelope glycoprotein.
    Cell. 1997 Apr 18;89(2):263-73 PMID: 9108481
  34. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.
    Science. 1998 Jun 19;280(5371):1884-8 PMID: 9632381
  35. Generation of human monoclonal antibodies to human immunodeficiency virus.
    Proc Natl Acad Sci U S A. 1989 Mar;86(5):1624-8 PMID: 2922401
  36. Structure of rotavirus outer-layer protein VP7 bound with a neutralizing Fab.
    Science. 2009 Jun 12;324(5933):1444-7 PMID: 19520960
  37. A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition.
    Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10537-41 PMID: 1438243
  38. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.
    N Engl J Med. 2009 Dec 3;361(23):2209-20 PMID: 19843557
  39. Features and development of Coot.
    Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501 PMID: 20383002
  40. Oligomeric and conformational properties of a proteolytically mature, disulfide-stabilized human immunodeficiency virus type 1 gp140 envelope glycoprotein.
    J Virol. 2002 Aug;76(15):7760-76 PMID: 12097589
  41. Novel therapies based on mechanisms of HIV-1 cell entry.
    N Engl J Med. 2003 May 29;348(22):2228-38 PMID: 12773651
  42. Conserved and exposed epitopes on intact, native, primary human immunodeficiency virus type 1 virions of group M.
    J Virol. 2000 Aug;74(15):7096-107 PMID: 10888650
  43. Viral membrane fusion.
    Nat Struct Mol Biol. 2008 Jul;15(7):690-8 PMID: 18596815
  44. Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.
    J Virol. 2004 Oct;78(19):10724-37 PMID: 15367639
  45. Electron-density map interpretation.
    Methods Enzymol. 1997;277:173-208 PMID: 18488310
  46. Atomic structure of the ectodomain from HIV-1 gp41.
    Nature. 1997 May 22;387(6631):426-30 PMID: 9163431
  47. Mechanism of membrane fusion by viral envelope proteins.
    Adv Virus Res. 2005;64:231-61 PMID: 16139596
  48. PHENIX: a comprehensive Python-based system for macromolecular structure solution.
    Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21 PMID: 20124702
  49. HIV entry and its inhibition.
    Cell. 1998 May 29;93(5):681-4 PMID: 9630213
  50. Role of HIV membrane in neutralization by two broadly neutralizing antibodies.
    Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20234-9 PMID: 19906992
  51. A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies.
    Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3739-44 PMID: 18322015
  52. Antibody neutralization and escape by HIV-1.
    Nature. 2003 Mar 20;422(6929):307-12 PMID: 12646921
  53. Antibody-dependent cellular cytotoxicity directed against cells expressing human immunodeficiency virus type 1 envelope of primary or laboratory-adapted strains by human and chimpanzee monoclonal antibodies of different epitope specificities.
    J Virol. 1998 Jan;72(1):286-93 PMID: 9420226
  54. Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis.
    Proc Natl Acad Sci U S A. 2006 May 23;103(21):8060-5 PMID: 16690741
  55. Anti-gp41 antibodies cloned from HIV-infected patients with broadly neutralizing serologic activity.
    J Virol. 2010 May;84(10):5032-42 PMID: 20219932
  56. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.
    Science. 2010 Aug 13;329(5993):811-7 PMID: 20616231
  57. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1.
    Science. 2010 Aug 13;329(5993):856-61 PMID: 20616233
  58. Kinetic dependence to HIV-1 entry inhibition.
    J Biol Chem. 2006 Sep 1;281(35):25813-21 PMID: 16803885
Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1950
Published
2010-12-00
Epub
2010-00-14
Pages
1486-91
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2997185
Subset
IM
Grants
NIAID NIH HHS · R01 AI036085 · United States
NIAID NIH HHS · AI36085 · United States
NIGMS NIH HHS · R01 GM083680 · United States
NIAID NIH HHS · AI084794 · United States
NIAID NIH HHS · R01 AI084794 · United States
NIGMS NIH HHS · GM083680 · United States
NIAID NIH HHS · R01 AI036085-14 · United States
External Links
PubMed source DOI: 10.1038/nsmb.1950 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2