Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike

Jeong Hyun Lee; Daniel P. Leaman; Arthur S. Kim; Alba Torrents de la Peña; Kwinten Sliepen; Anila Yasmeen; Ronald Derking; Alejandra Ramos; Steven W. de Taeye; Gabriel Ozorowski; Florian Klein; Dennis R. Burton; Michel C. Nussenzweig; Pascal Poignard; John P. Moore; Per Johan Klasse; Rogier W. Sanders; Michael B. Zwick; Ian A. Wilson; Andrew B. Ward

doi:https://doi.org/10.1038/ncomms9167

Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike

Jeong Hyun Lee, Daniel P. Leaman, Arthur S. Kim, Alba Torrents de la Peña, Kwinten Sliepen, Anila Yasmeen, Ronald Derking, Alejandra Ramos, Steven W. de Taeye, Gabriel Ozorowski, Florian Klein, Dennis R. Burton, Michel C. Nussenzweig, Pascal Poignard, John P. Moore, Per Johan Klasse, Rogier W. Sanders, Michael B. Zwick, Ian A. Wilson, Andrew B. Ward

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Abstract

The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120-gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 angstrom resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120-gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes

Original language	English
Pages (from-to)	8167
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9167
Publication status	Published - 2015

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Lee, J. H., Leaman, D. P., Kim, A. S., Torrents de la Peña, A., Sliepen, K., Yasmeen, A., Derking, R., Ramos, A., de Taeye, S. W., Ozorowski, G., Klein, F., Burton, D. R., Nussenzweig, M. C., Poignard, P., Moore, J. P., Klasse, P. J., Sanders, R. W., Zwick, M. B., Wilson, I. A., & Ward, A. B. (2015). Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike. Nature communications, 6, 8167. https://doi.org/10.1038/ncomms9167

@article{3634181987344fc3b01ff372a11fc128,

title = "Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike",

abstract = "The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120-gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 angstrom resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120-gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes",

author = "Lee, {Jeong Hyun} and Leaman, {Daniel P.} and Kim, {Arthur S.} and {Torrents de la Pe{\~n}a}, Alba and Kwinten Sliepen and Anila Yasmeen and Ronald Derking and Alejandra Ramos and {de Taeye}, {Steven W.} and Gabriel Ozorowski and Florian Klein and Burton, {Dennis R.} and Nussenzweig, {Michel C.} and Pascal Poignard and Moore, {John P.} and Klasse, {Per Johan} and Sanders, {Rogier W.} and Zwick, {Michael B.} and Wilson, {Ian A.} and Ward, {Andrew B.}",

year = "2015",

doi = "https://doi.org/10.1038/ncomms9167",

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Lee, JH, Leaman, DP, Kim, AS, Torrents de la Peña, A, Sliepen, K, Yasmeen, A, Derking, R, Ramos, A, de Taeye, SW, Ozorowski, G, Klein, F, Burton, DR, Nussenzweig, MC, Poignard, P, Moore, JP, Klasse, PJ, Sanders, RW, Zwick, MB, Wilson, IA & Ward, AB 2015, 'Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike', Nature communications, vol. 6, pp. 8167. https://doi.org/10.1038/ncomms9167

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AU - Lee, Jeong Hyun

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AU - Kim, Arthur S.

AU - Torrents de la Peña, Alba

AU - Sliepen, Kwinten

AU - Yasmeen, Anila

AU - Derking, Ronald

AU - Ramos, Alejandra

AU - de Taeye, Steven W.

AU - Ozorowski, Gabriel

AU - Klein, Florian

AU - Burton, Dennis R.

AU - Nussenzweig, Michel C.

AU - Poignard, Pascal

AU - Moore, John P.

AU - Klasse, Per Johan

AU - Sanders, Rogier W.

AU - Zwick, Michael B.

AU - Wilson, Ian A.

AU - Ward, Andrew B.

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AB - The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120-gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 angstrom resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120-gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes

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DO - https://doi.org/10.1038/ncomms9167

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