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PMID: 18322015 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 10 ·2008-03-11 ·Pages 3739-44

Frey G, Peng H, Rits-Volloch S, Morelli M, Cheng Y, Chen B

Abstract

Most antibodies induced by HIV-1 are ineffective at preventing initiation or spread of infection because they are either nonneutralizing or narrowly isolate-specific. Rare, "broadly neutralizing" antibodies have been detected that recognize relatively conserved regions on the envelope glycoprotein. Using stringently characterized, homogeneous preparations of trimeric HIV-1 envelope protein in relevant conformations, we have analyzed the molecular mechanism of neutralization by two of these antibodies, 2F5 and 4E10. We find that their epitopes, in the membrane-proximal segment of the envelope protein ectodomain, are exposed only on a form designed to mimic an intermediate state during viral entry. These results help explain the rarity of 2F5- and 4E10-like antibody responses and suggest a strategy for eliciting them.

MeSH Terms
Antibodies, Monoclonal/immunology Binding Sites, Antibody HIV Antibodies/immunology HIV Antigens/immunology HIV Envelope Protein gp41/chemistry,immunology HIV-1/immunology Kinetics Ligands Neutralization Tests Protein Structure, Quaternary Protein Structure, Secondary Recombinant Fusion Proteins/chemistry,immunology Surface Plasmon Resonance env Gene Products, Human Immunodeficiency Virus/chemistry
Chemicals
Antibodies, Monoclonal HIV Antibodies HIV Antigens HIV Envelope Protein gp41 Ligands Recombinant Fusion Proteins env Gene Products, Human Immunodeficiency Virus gp140 envelope protein, Human immunodeficiency virus 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Frey Gary
Laboratory of Molecular Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115, USA.
Peng Hanqin
Rits-Volloch Sophia
Morelli Marco
Cheng Yifan
Chen Bing
References (39)
39 references, click to expand
  1. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody.
    Science. 1994 Nov 11;266(5187):1024-7 PMID: 7973652
  2. Restraining the conformation of HIV-1 gp120 by removing a flexible loop.
    EMBO J. 2006 Oct 18;25(20):5026-35 PMID: 17006538
  3. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies.
    Science. 2005 Jun 24;308(5730):1906-8 PMID: 15860590
  4. A chimeric protein of simian immunodeficiency virus envelope glycoprotein gp140 and Escherichia coli aspartate transcarbamoylase.
    J Virol. 2004 May;78(9):4508-16 PMID: 15078931
  5. 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
  6. Expression, purification, and characterization of gp160e, the soluble, trimeric ectodomain of the simian immunodeficiency virus envelope glycoprotein, gp160.
    J Biol Chem. 2000 Nov 10;275(45):34946-53 PMID: 10944528
  7. Interactions of human antibodies, epitope exposure, antibody binding and neutralization of primary isolate HIV-1 virions.
    AIDS. 2002 Dec 6;16(18):2409-17 PMID: 12461414
  8. Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding.
    J Virol. 1993 Jul;67(7):3978-88 PMID: 7685405
  9. Epitope exposure on functional, oligomeric HIV-1 gp41 molecules.
    Virology. 1995 Jan 10;206(1):713-7 PMID: 7530400
  10. Exposure of the membrane-proximal external region of HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion.
    Biochemistry. 2007 Feb 6;46(5):1398-401 PMID: 17260969
  11. Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket.
    Cell. 1999 Oct 1;99(1):103-15 PMID: 10520998
  12. The stoichiometry of trimeric SIV glycoprotein interaction with CD4 differs from that of anti-envelope antibody Fab fragments.
    J Biol Chem. 2001 Nov 16;276(46):42667-76 PMID: 11544255
  13. 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
  14. 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
  15. HIV-1 Envgp140 trimers elicit neutralizing antibodies without efficient induction of conformational antibodies.
    Vaccine. 2006 Jun 29;24(26):5442-51 PMID: 16621193
  16. 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
  17. Conformational constraints imposed on a pan-neutralizing HIV-1 antibody epitope result in increased antigenicity but not neutralizing response.
    Vaccine. 2005 Feb 18;23(13):1559-73 PMID: 15694508
  18. Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies.
    J Virol. 2004 Dec;78(23):13232-52 PMID: 15542675
  19. Expression and characterisation of recombinant oligomeric envelope glycoproteins derived from primary isolates of HIV-1.
    Vaccine. 2004 Feb 25;22(8):1032-46 PMID: 15161081
  20. Structural definition of a conserved neutralization epitope on HIV-1 gp120.
    Nature. 2007 Feb 15;445(7129):732-7 PMID: 17301785
  21. Binding of the 2F5 monoclonal antibody to native and fusion-intermediate forms of human immunodeficiency virus type 1 gp41: implications for fusion-inducing conformational changes.
    J Virol. 2004 Mar;78(5):2627-31 PMID: 14963170
  22. Genetic evidence that interhelical packing interactions in the gp41 core are critical for transition of the human immunodeficiency virus type 1 envelope glycoprotein to the fusion-active state.
    J Virol. 2002 Jul;76(14):7356-62 PMID: 12072535
  23. 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
  24. Novel therapies based on mechanisms of HIV-1 cell entry.
    N Engl J Med. 2003 May 29;348(22):2228-38 PMID: 12773651
  25. 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
  26. 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
  27. Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion.
    Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):13938-43 PMID: 16963566
  28. Analyses of the antigenicity of influenza haemagglutinin at the pH optimum for virus-mediated membrane fusion.
    J Gen Virol. 1983 Aug;64 (Pt 8):1657-62 PMID: 6192202
  29. Mechanism of membrane fusion by viral envelope proteins.
    Adv Virus Res. 2005;64:231-61 PMID: 16139596
  30. HIV entry and its inhibition.
    Cell. 1998 May 29;93(5):681-4 PMID: 9630213
  31. Structure of the dengue virus envelope protein after membrane fusion.
    Nature. 2004 Jan 22;427(6972):313-9 PMID: 14737159
  32. Antibody neutralization and escape by HIV-1.
    Nature. 2003 Mar 20;422(6929):307-12 PMID: 12646921
  33. Highly stable trimers formed by human immunodeficiency virus type 1 envelope glycoproteins fused with the trimeric motif of T4 bacteriophage fibritin.
    J Virol. 2002 May;76(9):4634-42 PMID: 11932429
  34. Structure of the prefusion form of the vesicular stomatitis virus glycoprotein G.
    Science. 2007 Feb 9;315(5813):843-8 PMID: 17289996
  35. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.
    Annu Rev Biochem. 2000;69:531-69 PMID: 10966468
  36. Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41.
    Immunity. 2005 Feb;22(2):163-73 PMID: 15723805
  37. Antigenic properties of the human immunodeficiency virus transmembrane glycoprotein during cell-cell fusion.
    J Virol. 2002 Dec;76(23):12123-34 PMID: 12414953
  38. Kinetic dependence to HIV-1 entry inhibition.
    J Biol Chem. 2006 Sep 1;281(35):25813-21 PMID: 16803885
  39. Glycosylation inhibitors and neuraminidase enhance human immunodeficiency virus type 1 binding and neutralization by mannose-binding lectin.
    J Gen Virol. 2003 Feb;84(Pt 2):353-360 PMID: 12560567
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0800255105
Published
2008-03-11
Epub
2008-00-05
Pages
3739-44
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2268799
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0800255105 PMC Full Text View journal details
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