Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing

Xueling Wu; Tongqing Zhou; Jiang Zhu; Baoshan Zhang; Ivelin Georgiev; Charlene Wang; Xuejun Chen; Nancy S. Longo; Mark Louder; Krisha McKee; Sijy O'Dell; Stephen Perfetto; Stephen D. Schmidt; Wei Shi; Lan Wu; Yongping Yang; Zhi Yong Yang; Zhongjia Yang; Zhenhai Zhang; Mattia Bonsignori; John A. Crump; Saidi H. Kapiga; Noel E. Sam; Barton F. Haynes; Melissa Simek; Dennis R. Burton; Wayne C. Koff; Nicole A. Doria-Rose; Mark Connors; James C. Mullikin; Gary J. Nabel; Mario Roederer; Lawrence Shapiro; Peter D. Kwong; John R. Mascola

doi:10.1126/science.1207532

Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing

Xueling Wu, Tongqing Zhou, Jiang Zhu, Baoshan Zhang, Ivelin Georgiev, Charlene Wang, Xuejun Chen, Nancy S. Longo, Mark Louder, Krisha McKee, Sijy O'Dell, Stephen Perfetto, Stephen D. Schmidt, Wei Shi, Lan Wu, Yongping Yang, Zhi Yong Yang, Zhongjia Yang, Zhenhai Zhang, Mattia BonsignoriJohn A. Crump, Saidi H. Kapiga, Noel E. Sam, Barton F. Haynes, Melissa Simek, Dennis R. Burton, Wayne C. Koff, Nicole A. Doria-Rose, Mark Connors, James C. Mullikin, Gary J. Nabel, Mario Roederer, Lawrence Shapiro, Peter D. Kwong, John R. Mascola

Research output: Contribution to journal › Article › peer-review

627 Scopus citations

Abstract

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

Original language	English (US)
Pages (from-to)	1593-1602
Number of pages	10
Journal	Science
Volume	333
Issue number	6049
DOIs	https://doi.org/10.1126/science.1207532
State	Published - Sep 16 2011
Externally published	Yes

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Wu, X., Zhou, T., Zhu, J., Zhang, B., Georgiev, I., Wang, C., Chen, X., Longo, N. S., Louder, M., McKee, K., O'Dell, S., Perfetto, S., Schmidt, S. D., Shi, W., Wu, L., Yang, Y., Yang, Z. Y., Yang, Z., Zhang, Z., ... Mascola, J. R. (2011). Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science, 333(6049), 1593-1602. https://doi.org/10.1126/science.1207532

Wu, X, Zhou, T, Zhu, J, Zhang, B, Georgiev, I, Wang, C, Chen, X, Longo, NS, Louder, M, McKee, K, O'Dell, S, Perfetto, S, Schmidt, SD, Shi, W, Wu, L, Yang, Y, Yang, ZY, Yang, Z, Zhang, Z, Bonsignori, M, Crump, JA, Kapiga, SH, Sam, NE, Haynes, BF, Simek, M, Burton, DR, Koff, WC, Doria-Rose, NA, Connors, M, Mullikin, JC, Nabel, GJ, Roederer, M, Shapiro, L, Kwong, PD & Mascola, JR 2011, 'Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing', Science, vol. 333, no. 6049, pp. 1593-1602. https://doi.org/10.1126/science.1207532

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title = "Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing",

abstract = "Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.",

author = "Xueling Wu and Tongqing Zhou and Jiang Zhu and Baoshan Zhang and Ivelin Georgiev and Charlene Wang and Xuejun Chen and Longo, {Nancy S.} and Mark Louder and Krisha McKee and Sijy O'Dell and Stephen Perfetto and Schmidt, {Stephen D.} and Wei Shi and Lan Wu and Yongping Yang and Yang, {Zhi Yong} and Zhongjia Yang and Zhenhai Zhang and Mattia Bonsignori and Crump, {John A.} and Kapiga, {Saidi H.} and Sam, {Noel E.} and Haynes, {Barton F.} and Melissa Simek and Burton, {Dennis R.} and Koff, {Wayne C.} and Doria-Rose, {Nicole A.} and Mark Connors and Mullikin, {James C.} and Nabel, {Gary J.} and Mario Roederer and Lawrence Shapiro and Kwong, {Peter D.} and Mascola, {John R.}",

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AU - Chen, Xuejun

AU - Longo, Nancy S.

AU - Louder, Mark

AU - McKee, Krisha

AU - O'Dell, Sijy

AU - Perfetto, Stephen

AU - Schmidt, Stephen D.

AU - Shi, Wei

AU - Wu, Lan

AU - Yang, Yongping

AU - Yang, Zhi Yong

AU - Yang, Zhongjia

AU - Zhang, Zhenhai

AU - Bonsignori, Mattia

AU - Crump, John A.

AU - Kapiga, Saidi H.

AU - Sam, Noel E.

AU - Haynes, Barton F.

AU - Simek, Melissa

AU - Burton, Dennis R.

AU - Koff, Wayne C.

AU - Doria-Rose, Nicole A.

AU - Connors, Mark

AU - Mullikin, James C.

AU - Nabel, Gary J.

AU - Roederer, Mario

AU - Shapiro, Lawrence

AU - Kwong, Peter D.

AU - Mascola, John R.

PY - 2011/9/16

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N2 - Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

AB - Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

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Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing

Abstract

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