Universität zu Köln

Freund, Natalia T., Horwitz, Joshua A., Nogueira, Lilian, Sievers, Stuart A., Scharf, Louise, Scheid, Johannes F., Gazumyan, Anna, Liu, Cassie ORCID: 0000-0003-3907-9409, Velinzon, Klara, Goldenthal, Ariel, Sanders, Rogier W., Moore, John P., Bjorkman, Pamela J., Seaman, Michael S., Walker, Bruce D., Klein, Florian and Nussenzweig, Michel C. (2015). A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo. PLoS Pathog., 11 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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Abstract

The CD4 binding site (CD4bs) on the envelope glycoprotein is a major site of vulnerability that is conserved among different HIV-1 isolates. Many broadly neutralizing antibodies (bNAbs) to the CD4bs belong to the VRC01 class, sharing highly restricted origins, recognition mechanisms and viral escape pathways. We sought to isolate new anti-CD4bs bNAbs with different origins and mechanisms of action. Using a gp120 2CC core as bait, we isolated antibodies encoded by IGVH3-21 and IGVL3-1 genes with long CDRH3s that depend on the presence of the N-linked glycan at position-276 for activity. This binding mode is similar to the previously identified antibody HJ16, however the new antibodies identified herein are more potent and broad. The most potent variant, 179NC75, had a geometric mean IC80 value of 0.42 mu g/ml against 120 Tier-2 HIV-1 pseudoviruses in the TZM.bl assay. Although this group of CD4bs glycan-dependent antibodies can be broadly and potently neutralizing in vitro, their in vivo activity has not been tested to date. Here, we report that 179NC75 is highly active when administered to HIV-1-infected humanized mice, where it selects for escape variants that lack a glycan site at position-276. The same glycan was absent from the virus isolated from the 179NC75 donor, implying that the antibody also exerts selection pressure in humans.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Freund, Natalia T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Horwitz, Joshua A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nogueira, Lilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Sievers, Stuart A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scharf, Louise UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheid, Johannes F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gazumyan, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Cassie UNSPECIFIED orcid.org/0000-0003-3907-9409 UNSPECIFIED Velinzon, Klara UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldenthal, Ariel UNSPECIFIED UNSPECIFIED UNSPECIFIED Sanders, Rogier W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moore, John P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bjorkman, Pamela J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seaman, Michael S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Walker, Bruce D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Nussenzweig, Michel C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-392310
DOI:	10.1371/journal.ppat.1005238
Journal or Publication Title:	PLoS Pathog.
Volume:	11
Number:	10
Date:	2015
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7374
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MONOCLONAL-ANTIBODIES; STRUCTURAL BASIS; B-CELLS; BROAD; RECOGNITION; EPITOPE; EXPRESSION; EVOLUTION; INFECTION; REVEALS Multiple languages Microbiology; Parasitology; Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39231