Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

Immunity. 2019 Jun 18;50(6):1513-1529.e9. doi: 10.1016/j.immuni.2019.04.014. Epub 2019 May 21.


Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

Keywords: Env trimer; HIV-1; HIV-1 Env silent face; HIV-1 vaccine; broadly neutralizing antibody; cryo-EM; glycan recognition; humanized mice; immunotherapy.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / isolation & purification
  • Antibody Affinity / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Epitopes / chemistry
  • Epitopes / immunology
  • Glycosylation
  • HIV Antibodies / immunology*
  • HIV Antibodies / isolation & purification
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / classification
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Humans
  • Models, Molecular
  • Phylogeny
  • Polysaccharides / chemistry
  • Polysaccharides / metabolism
  • Protein Binding / immunology
  • Protein Conformation
  • env Gene Products, Human Immunodeficiency Virus / chemistry
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology*
  • env Gene Products, Human Immunodeficiency Virus / metabolism


  • Antibodies, Neutralizing
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Polysaccharides
  • env Gene Products, Human Immunodeficiency Virus