Restriction of hiv-1 escape by a highly broad and potent neutralizing antibody

  • 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.
Metadaten
Author:Philipp Frederik SchommersORCiDGND, Henning GrüllORCiDGND, Morgan E. Abernathy, My-Kim Tran, Adam S. Dingens, Harry B. Gristick, Christopher O. Barnes, Till Schoofs, Maike Schlotz, Kanika VanshyllaORCiD, Christoph KreerORCiDGND, Daniela Weiland, Udo Holtick, Christof Scheid, Markus Valter, Marit J. van Gils, Rogier W. Sanders, Jörg Janne VehreschildORCiDGND, Oliver Andreas CornelyORCiDGND, Clara Lehmann, Gerd FätkenheuerORCiDGND, Michael S. Seaman, Jesse D. Bloom, Pamela J. Bjorkman, Florian Klein
URN:urn:nbn:de:hebis:30:3-530735
DOI:https://doi.org/10.1016/j.cell.2020.01.010
ISSN:1097-4172
ISSN:0092-8674
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/32004464
Parent Title (English):Cell
Publisher:Cell Press ; Elsevier
Place of publication:[Cambridge, Mass.] ; New York, NY
Document Type:Article
Language:English
Year of Completion:2020
Date of first Publication:2020/01/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/03/09
Tag: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
Volume:180
Issue:3
Page Number:42
First Page:471
Last Page:489.e22
Note:
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
HeBIS-PPN:464655579
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0