Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

Shanshan Lang; Jia Xie; Xueyong Zhu; Nicholas C. Wu; Richard A. Lerner; Ian A. Wilson

doi:10.1016/j.celrep.2017.08.084

Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in V_H1-69 Antibody Orientation on the HA Stem

Shanshan Lang
, Jia Xie
, Xueyong Zhu
, Nicholas C. Wu
, Richard A. Lerner
, Ian A. Wilson

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

Abstract

Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here, we describe a new V_H1-69 antibody 27F3 that broadly recognizes heterosubtypic hemagglutinins (HAs) from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates that 27F3 shares the key binding features observed in other V_H1-69 antibodies to the HA stem. Compared to other V_H1-69 antibodies, the 27F3 V_H domain interacts with the HA stem in a distinct orientation, which alters its epitope and may have influenced its breadth. The diverse rotations of V_H1-69 antibodies on the HA stem epitope highlight the different ways that this antibody family can evolve to broadly neutralize influenza A viruses. These results have important implications for understanding how to elicit broad antibody responses against influenza virus.

Original language	English (US)
Pages (from-to)	2935-2943
Number of pages	9
Journal	Cell Reports
Volume	20
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2017.08.084
State	Published - Sep 19 2017
Externally published	Yes

Keywords

antibody family
broadly neutralizing antibodies
crystal structure
hemagglutinin
influenza virus
phage display
V1-69

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Online availability

10.1016/j.celrep.2017.08.084

Library availability

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Cite this

@article{89355f9e6fdb445ba445fe1a10b267fd,

title = "Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem",

abstract = "Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here, we describe a new VH1-69 antibody 27F3 that broadly recognizes heterosubtypic hemagglutinins (HAs) from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates that 27F3 shares the key binding features observed in other VH1-69 antibodies to the HA stem. Compared to other VH1-69 antibodies, the 27F3 VH domain interacts with the HA stem in a distinct orientation, which alters its epitope and may have influenced its breadth. The diverse rotations of VH1-69 antibodies on the HA stem epitope highlight the different ways that this antibody family can evolve to broadly neutralize influenza A viruses. These results have important implications for understanding how to elicit broad antibody responses against influenza virus.",

keywords = "antibody family, broadly neutralizing antibodies, crystal structure, hemagglutinin, influenza virus, phage display, V1-69",

author = "Shanshan Lang and Jia Xie and Xueyong Zhu and Wu, \{Nicholas C.\} and Lerner, \{Richard A.\} and Wilson, \{Ian A.\}",

note = "We thank Henry Tien from the Wilson lab and robotics core at the Joint Center for Structural Genomics (JCSG) for automated crystal screening, Wenli Yu and Yuanzi Huang (Wilson lab, TSRI) for excellent technical support, and Dr. Jesse Bloom (Fred Hutchinson Cancer Research Center) for the pHH21-PB1flank-eGFP plasmid, 293T-CMV-PB1 cells, and MDCK-SIAT1-CMV-PB1 cells. X-ray diffraction data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL). Use of the SSRL SLAC National Accelerator Laboratory is supported by the U.S. Department of Energy (DOE) Office of Science, Office of Basic Energy Sciences (under contract no. DE-AC02-76SF00515 ). The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH , National Institute of General Medical Sciences (NIGMS; including P41GM103393 ). The research was supported by NIH R56 AI117675 (to I.A.W.) and the Skaggs Institute for Chemical Biology . The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS, NIAID, or NIH. This is manuscript 29507 from The Scripps Research Institute.",

year = "2017",

month = sep,

day = "19",

doi = "10.1016/j.celrep.2017.08.084",

language = "English (US)",

volume = "20",

pages = "2935--2943",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

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T1 - Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

AU - Lang, Shanshan

AU - Xie, Jia

AU - Zhu, Xueyong

AU - Wu, Nicholas C.

AU - Lerner, Richard A.

AU - Wilson, Ian A.

N1 - We thank Henry Tien from the Wilson lab and robotics core at the Joint Center for Structural Genomics (JCSG) for automated crystal screening, Wenli Yu and Yuanzi Huang (Wilson lab, TSRI) for excellent technical support, and Dr. Jesse Bloom (Fred Hutchinson Cancer Research Center) for the pHH21-PB1flank-eGFP plasmid, 293T-CMV-PB1 cells, and MDCK-SIAT1-CMV-PB1 cells. X-ray diffraction data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL). Use of the SSRL SLAC National Accelerator Laboratory is supported by the U.S. Department of Energy (DOE) Office of Science, Office of Basic Energy Sciences (under contract no. DE-AC02-76SF00515 ). The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH , National Institute of General Medical Sciences (NIGMS; including P41GM103393 ). The research was supported by NIH R56 AI117675 (to I.A.W.) and the Skaggs Institute for Chemical Biology . The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS, NIAID, or NIH. This is manuscript 29507 from The Scripps Research Institute.

PY - 2017/9/19

Y1 - 2017/9/19

N2 - Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here, we describe a new VH1-69 antibody 27F3 that broadly recognizes heterosubtypic hemagglutinins (HAs) from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates that 27F3 shares the key binding features observed in other VH1-69 antibodies to the HA stem. Compared to other VH1-69 antibodies, the 27F3 VH domain interacts with the HA stem in a distinct orientation, which alters its epitope and may have influenced its breadth. The diverse rotations of VH1-69 antibodies on the HA stem epitope highlight the different ways that this antibody family can evolve to broadly neutralize influenza A viruses. These results have important implications for understanding how to elicit broad antibody responses against influenza virus.

AB - Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here, we describe a new VH1-69 antibody 27F3 that broadly recognizes heterosubtypic hemagglutinins (HAs) from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates that 27F3 shares the key binding features observed in other VH1-69 antibodies to the HA stem. Compared to other VH1-69 antibodies, the 27F3 VH domain interacts with the HA stem in a distinct orientation, which alters its epitope and may have influenced its breadth. The diverse rotations of VH1-69 antibodies on the HA stem epitope highlight the different ways that this antibody family can evolve to broadly neutralize influenza A viruses. These results have important implications for understanding how to elicit broad antibody responses against influenza virus.

KW - antibody family

KW - broadly neutralizing antibodies

KW - crystal structure

KW - hemagglutinin

KW - influenza virus

KW - phage display

KW - V1-69

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DO - 10.1016/j.celrep.2017.08.084

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