Philipp Frederik Schommers, Henning Grüll, 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 Valter, Marit J. van Gils, Rogier W. Sanders, Jörg Janne Vehreschild, Oliver Andreas Cornely, Clara Lehmann, Gerd Fätkenheuer, Michael S. Seaman, Jesse D. Bloom, Pamela J. Bjorkman, Florian Klein
- 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.
MetadatenAuthor: | 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 |
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URN: | urn:nbn:de:hebis:30:3-530735 |
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DOI: | https://doi.org/10.1016/j.cell.2020.01.010 |
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ISSN: | 1097-4172 |
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ISSN: | 0092-8674 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/32004464 |
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Parent Title (English): | Cell |
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Publisher: | Cell Press ; Elsevier |
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Place of publication: | [Cambridge, Mass.] ; New York, NY |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2020 |
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Date of first Publication: | 2020/01/30 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2020/03/09 |
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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 |
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Volume: | 180 |
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Issue: | 3 |
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Page Number: | 42 |
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First Page: | 471 |
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Last Page: | 489.e22 |
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Note: | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
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HeBIS-PPN: | 464655579 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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