HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

Peter D. Kwong, Michael L. Doyle, David J. Casper, Claudia Cicala, Stephanie A. Leavitt, Shahzad Majeed, Tavis D. Steenbeke, Miro Venturi, Irwin Chaiken, Michael Fung, Hermann Katinger, Paul W I H Parren, James Robinson, Donald Van Ryk, Liping Wang, Dennis R. Burton, Ernesto I Freire, Richard Wyatt, Joseph Sodroski, Wayne A. HendricksonJames Arthos

Research output: Contribution to journalArticle

Abstract

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.

Original languageEnglish (US)
Pages (from-to)678-682
Number of pages5
JournalNature
Volume420
Issue number6916
DOIs
StatePublished - Dec 12 2002

Fingerprint

HIV-1
Binding Sites
Antibodies
Glycoproteins
Antibody Binding Sites
Virus Receptors
Cell Surface Receptors
Entropy
Thermodynamics
Acquired Immunodeficiency Syndrome
Viruses

ASJC Scopus subject areas

  • General

Cite this

Kwong, P. D., Doyle, M. L., Casper, D. J., Cicala, C., Leavitt, S. A., Majeed, S., ... Arthos, J. (2002). HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature, 420(6916), 678-682. https://doi.org/10.1038/nature01188

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. / Kwong, Peter D.; Doyle, Michael L.; Casper, David J.; Cicala, Claudia; Leavitt, Stephanie A.; Majeed, Shahzad; Steenbeke, Tavis D.; Venturi, Miro; Chaiken, Irwin; Fung, Michael; Katinger, Hermann; Parren, Paul W I H; Robinson, James; Van Ryk, Donald; Wang, Liping; Burton, Dennis R.; Freire, Ernesto I; Wyatt, Richard; Sodroski, Joseph; Hendrickson, Wayne A.; Arthos, James.

In: Nature, Vol. 420, No. 6916, 12.12.2002, p. 678-682.

Research output: Contribution to journalArticle

Kwong, PD, Doyle, ML, Casper, DJ, Cicala, C, Leavitt, SA, Majeed, S, Steenbeke, TD, Venturi, M, Chaiken, I, Fung, M, Katinger, H, Parren, PWIH, Robinson, J, Van Ryk, D, Wang, L, Burton, DR, Freire, EI, Wyatt, R, Sodroski, J, Hendrickson, WA & Arthos, J 2002, 'HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites', Nature, vol. 420, no. 6916, pp. 678-682. https://doi.org/10.1038/nature01188
Kwong PD, Doyle ML, Casper DJ, Cicala C, Leavitt SA, Majeed S et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature. 2002 Dec 12;420(6916):678-682. https://doi.org/10.1038/nature01188
Kwong, Peter D. ; Doyle, Michael L. ; Casper, David J. ; Cicala, Claudia ; Leavitt, Stephanie A. ; Majeed, Shahzad ; Steenbeke, Tavis D. ; Venturi, Miro ; Chaiken, Irwin ; Fung, Michael ; Katinger, Hermann ; Parren, Paul W I H ; Robinson, James ; Van Ryk, Donald ; Wang, Liping ; Burton, Dennis R. ; Freire, Ernesto I ; Wyatt, Richard ; Sodroski, Joseph ; Hendrickson, Wayne A. ; Arthos, James. / HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. In: Nature. 2002 ; Vol. 420, No. 6916. pp. 678-682.
@article{6b264b4854f44784b64b81933b000ddc,
title = "HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites",
abstract = "The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.",
author = "Kwong, {Peter D.} and Doyle, {Michael L.} and Casper, {David J.} and Claudia Cicala and Leavitt, {Stephanie A.} and Shahzad Majeed and Steenbeke, {Tavis D.} and Miro Venturi and Irwin Chaiken and Michael Fung and Hermann Katinger and Parren, {Paul W I H} and James Robinson and {Van Ryk}, Donald and Liping Wang and Burton, {Dennis R.} and Freire, {Ernesto I} and Richard Wyatt and Joseph Sodroski and Hendrickson, {Wayne A.} and James Arthos",
year = "2002",
month = "12",
day = "12",
doi = "10.1038/nature01188",
language = "English (US)",
volume = "420",
pages = "678--682",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6916",

}

TY - JOUR

T1 - HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

AU - Kwong, Peter D.

AU - Doyle, Michael L.

AU - Casper, David J.

AU - Cicala, Claudia

AU - Leavitt, Stephanie A.

AU - Majeed, Shahzad

AU - Steenbeke, Tavis D.

AU - Venturi, Miro

AU - Chaiken, Irwin

AU - Fung, Michael

AU - Katinger, Hermann

AU - Parren, Paul W I H

AU - Robinson, James

AU - Van Ryk, Donald

AU - Wang, Liping

AU - Burton, Dennis R.

AU - Freire, Ernesto I

AU - Wyatt, Richard

AU - Sodroski, Joseph

AU - Hendrickson, Wayne A.

AU - Arthos, James

PY - 2002/12/12

Y1 - 2002/12/12

N2 - The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.

AB - The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.

UR - http://www.scopus.com/inward/record.url?scp=0037069682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037069682&partnerID=8YFLogxK

U2 - 10.1038/nature01188

DO - 10.1038/nature01188

M3 - Article

C2 - 12478295

AN - SCOPUS:0037069682

VL - 420

SP - 678

EP - 682

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6916

ER -