Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Cell. 2020 Feb 6;180(3):471-489.e22. doi: 10.1016/j.cell.2020.01.010. Epub 2020 Jan 30.


Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.

Keywords: CD4 binding site; HIV-1; HIV-1 escape restriction; broadly neutralizing antibodies; cryogenic electron microscopy; deep mutational scanning; escape mutations; humanized mice; immunotherapy; mutational antigenic profiling.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Binding Sites
  • Broadly Neutralizing Antibodies / immunology*
  • CD4 Antigens / metabolism
  • CHO Cells
  • Cohort Studies
  • Cricetulus
  • Epitopes / immunology
  • Female
  • HEK293 Cells
  • HIV Antibodies / immunology*
  • HIV Infections / immunology*
  • HIV Infections / prevention & control
  • HIV Infections / virology
  • HIV-1 / immunology*
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Middle Aged
  • Mutation
  • Protein Binding / immunology
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology*


  • Antibodies, Monoclonal
  • Broadly Neutralizing Antibodies
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus