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A human antibody to the CD4 binding site of gp120 capable of highly potent but sporadic cross clade neutralization of primary HIV-1

Academic Article
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Overview

authors

  • Gach, J. S.
  • Quendler, H.
  • Tong, T.
  • Narayan, K. M.
  • Du, S. X.
  • Whalen, R. G.
  • Binley, J. M.
  • Forthal, D. N.
  • Poignard, Pascal
  • Zwick, Michael

publication date

  • August 2013

journal

  • PLoS One  Journal

abstract

  • Primary isolates of HIV-1 resist neutralization by most antibodies to the CD4 binding site (CD4bs) on gp120 due to occlusion of this site on the trimeric spike. We describe 1F7, a human CD4bs monoclonal antibody that was found to be exceptionally potent against the HIV-1 primary isolate JR-FL. However, 1F7 failed to neutralize a patient-matched primary isolate, JR-CSF even though the two isolates differ by <10% in gp120 at the protein level. In an HIV-1 cross clade panel (n = 157), 1F7 exhibited moderate breadth, but occasionally achieved considerable potency. In binding experiments using monomeric gp120s of select resistant isolates and domain-swap chimeras between JR-FL and JR-CSF, recognition by 1F7 was limited by sequence polymorphisms involving at least the C2 region of Env. Putative N-linked glycosylation site (PNGS) mutations, notably at position 197, allowed 1F7 to neutralize JR-CSF potently without improving binding to the cognate, monomeric gp120. In contrast, flow cytometry experiments using the same PNGS mutants revealed that 1F7 binding is enhanced on cognate trimeric Env. BN-PAGE mobility shift experiments revealed that 1F7 is sensitive to the diagnostic mutation D368R in the CD4 binding loop of gp120. Our data on 1F7 reinforce how exquisitely targeted CD4bs antibodies must be to achieve cross neutralization of two closely related primary isolates. High-resolution analyses of trimeric Env that show the orientation of glycans and polymorphic elements of the CD4bs that affect binding to antibodies like 1F7 are desirable to understand how to promote immunogenicity of more conserved elements of the CD4bs.

subject areas

  • Amino Acid Sequence
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibody Specificity
  • Antigens, CD4
  • Binding Sites, Antibody
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Glycosylation
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV-1
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Neutralization Tests
  • Protein Binding
  • Sequence Homology, Amino Acid
  • Species Specificity
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Identity

PubMed Central ID

  • PMC3753353

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0072054

PubMed ID

  • 23991039
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Additional Document Info

start page

  • e72054

volume

  • 8

issue

  • 8

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