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Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9

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Overview

related to degree

  • Lee, Jeong Hyun, Ph.D. in Chemical Biology, Scripps Research 2011 - 2016
  • Murin, Charles Daniel, Ph.D. in Biophysics, Scripps Research 2011 - 2016

authors

  • Julien, J. P.
  • Lee, Jeong Hyun
  • Cupo, A.
  • Murin, Charles Daniel
  • Derking, R.
  • Hoffenberg, S.
  • Caulfield, M. J.
  • King, C. R.
  • Marozsan, A. J.
  • Klasse, P. J.
  • Sanders, R. W.
  • Moore, J. P.
  • Wilson, Ian
  • Ward, Andrew

publication date

  • March 2013

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • PG9 is the founder member of an expanding family of glycan-dependent human antibodies that preferentially bind the HIV (HIV-1) envelope (Env) glycoprotein (gp) trimer and broadly neutralize the virus. Here, we show that a soluble SOSIP.664 gp140 trimer constructed from the Clade A BG505 sequence binds PG9 with high affinity (?11 nM), enabling structural and biophysical characterizations of the PG9:Env trimer complex. The BG505 SOSIP.664 gp140 trimer is remarkably stable as assessed by electron microscopy (EM) and differential scanning calorimetry. EM, small angle X-ray scattering, size exclusion chromatography with inline multiangle light scattering and isothermal titration calorimetry all indicate that only a single PG9 fragment antigen-binding (Fab) binds to the Env trimer. An ?18 ? EM reconstruction demonstrates that PG9 recognizes the trimer asymmetrically at its apex via contact with two of the three gp120 protomers, possibly contributing to its reported preference for a quaternary epitope. Molecular modeling and isothermal titration calorimetry binding experiments with an engineered PG9 mutant suggest that, in addition to the N156 and N160 glycan interactions observed in crystal structures of PG9 with a scaffolded V1/V2 domain, PG9 makes secondary interactions with an N160 glycan from an adjacent gp120 protomer in the antibody-trimer complex. Together, these structural and biophysical findings should facilitate the design of HIV-1 immunogens that possess all elements of the quaternary PG9 epitope required to induce broadly neutralizing antibodies against this region.
  • PG9 is the founder member of an expanding family of glycan-dependent human antibodies that preferentially bind the HIV (HIV-1) envelope (Env) glycoprotein (gp) trimer and broadly neutralize the virus. Here, we show that a soluble SOSIP.664 gp140 trimer constructed from the Clade A BG505 sequence binds PG9 with high affinity (∼11 nM), enabling structural and biophysical characterizations of the PG9:Env trimer complex. The BG505 SOSIP.664 gp140 trimer is remarkably stable as assessed by electron microscopy (EM) and differential scanning calorimetry. EM, small angle X-ray scattering, size exclusion chromatography with inline multiangle light scattering and isothermal titration calorimetry all indicate that only a single PG9 fragment antigen-binding (Fab) binds to the Env trimer. An ∼18 Å EM reconstruction demonstrates that PG9 recognizes the trimer asymmetrically at its apex via contact with two of the three gp120 protomers, possibly contributing to its reported preference for a quaternary epitope. Molecular modeling and isothermal titration calorimetry binding experiments with an engineered PG9 mutant suggest that, in addition to the N156 and N160 glycan interactions observed in crystal structures of PG9 with a scaffolded V1/V2 domain, PG9 makes secondary interactions with an N160 glycan from an adjacent gp120 protomer in the antibody-trimer complex. Together, these structural and biophysical findings should facilitate the design of HIV-1 immunogens that possess all elements of the quaternary PG9 epitope required to induce broadly neutralizing antibodies against this region.

subject areas

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Cell Line
  • Epitopes
  • HIV Antibodies
  • HIV-1
  • Humans
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • X-Ray Diffraction
  • env Gene Products, Human Immunodeficiency Virus
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Identity

PubMed Central ID

  • PMC3600498

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1217537110

PubMed ID

  • 23426631
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Additional Document Info

start page

  • 213

end page

  • 218

volume

  • 110

issue

  • 11

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