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

Abstract

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.

• Authors: Philipp Schommers, Henning Gruell, Morgan E Abernathy, My-Kim Tran, Adam S Dingens, Harry B Gristick, Christopher O Barnes, Till Schoofs, Maike Schlotz, Kanika Vanshylla, Christoph Kreer, Daniela Weiland, Udo Holtick, Christof Scheid, Markus M Valter, Marit J van Gils, Rogier W Sanders, Jörg J Vehreschild, Oliver A Cornely, Clara Lehmann, Gerd Fätkenheuer, Michael S Seaman, Jesse D Bloom, Pamela J Bjorkman, Florian Klein
• Journal: Cell (Cell) Vol. 180 Issue 3 Pg. 471-489.e22 (02 06 2020) ISSN: 1097-4172 [Electronic] United States
• PMID: 32004464 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 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, prevention & control, virology)
• HIV-1 (immunology)
• Heterografts
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Middle Aged
• Mutation
• Protein Binding (immunology)
• env Gene Products, Human Immunodeficiency Virus (genetics, immunology)