Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface

Nature. 2014 Nov 6;515(7525):138-42. doi: 10.1038/nature13601. Epub 2014 Sep 3.

Abstract

The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC50) <50 μg ml(-1). The median IC50 of neutralized viruses was 0.033 μg ml(-1), among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / chemistry
  • AIDS Vaccines / immunology
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / pharmacology
  • Antibody Affinity*
  • Antibody Specificity
  • CD4 Antigens / metabolism
  • Cell Line
  • Cell Membrane / virology
  • Conserved Sequence
  • Epitope Mapping
  • Epitopes / chemistry
  • Epitopes / immunology
  • HIV Antibodies / chemistry
  • HIV Antibodies / genetics
  • HIV Antibodies / immunology*
  • HIV Antibodies / pharmacology
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp41 / chemistry*
  • HIV Envelope Protein gp41 / immunology*
  • HIV-1 / drug effects
  • HIV-1 / immunology
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / genetics
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / ultrastructure
  • Inhibitory Concentration 50
  • Leukocytes, Mononuclear
  • Models, Molecular
  • Molecular Sequence Data
  • Receptors, CCR5 / metabolism
  • Virus Internalization / drug effects

Substances

  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • Immunoglobulin Fab Fragments
  • Receptors, CCR5

Associated data

  • GENBANK/KM001872
  • GENBANK/KM001873
  • GENBANK/KM001874
  • GENBANK/KM001875
  • GENBANK/KM001876
  • GENBANK/KM001877
  • GENBANK/KM001878
  • GENBANK/KM001879
  • GENBANK/KM001880
  • GENBANK/KM001881
  • GENBANK/KM001882
  • GENBANK/KM001883
  • GENBANK/KM001884
  • GENBANK/KM001885
  • GENBANK/KM001886
  • GENBANK/KM001887
  • GENBANK/KM516886
  • GENBANK/KM516887
  • GENBANK/KM516888
  • GENBANK/KM516889
  • GENBANK/KM516890
  • GENBANK/KM516891
  • GENBANK/KM516892
  • GENBANK/KM516893
  • GENBANK/KM516894
  • GENBANK/KM516895
  • GENBANK/KM516896
  • GENBANK/KM516897
  • PDB/4TOY