A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo
- Creators
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Freund, Natalia T.
- Horwitz, Joshua A.
- Nogueira, Lilian
- Sievers, Stuart A.
- Scharf, Louise
- Scheid, Johannes F.
- Gazumyan, Anna
- Liu, Cassie
- Velinzon, Klara
- Goldenthal, Ariel
- Sanders, Rogier W.
- Moore, John P.
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Bjorkman, Pamela J.
- Seaman, Michael S.
- Walker, Bruce D.
- Klein, Florian
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Nussenzweig, Michel C.
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 IC_(80) value of 0.42 μg/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.
Additional Information
© 2015 Freund et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: July 23, 2015; Accepted: September 28, 2015; Published: October 30, 2015. This research was supported by The Rockefeller University, by National Institutes of Health HIVRAD Grants 1 P01 AI100148 (to MCN and PJB) and AI110657 (JPM RWS) and by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant OPP1032144 (MSS). SAS was supported by a postdoctoral fellowship from the CA HIV/AIDS research program (CHRP F12-CT-214). MCN and BDW are Howard Hughes Medical Institute investigators. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank donor EB179 for his participation in this study, Leonidas Stamatatos for providing the VRC01gl antibody, Anthony West Jr for help with gene analyses, Jost Vielmetter and the Caltech Protein Expression Center for producing proteins and use of the Biacore T200, and Ari Halper-Stromberg for his constructive comments. We thank Florencia Pereyra from the Ragon institute and Arlene Hurley from Rockefeller University Hospital for coordinating sample transfer. Marit Van Gils for production and sharing of the SOSIP trimmers. N.T.F. Thanks O.F., T.P., A.T., and A.F, A.Y.F and A.A.F for their inspiration, love and support. Author Contributions: Conceived and designed the experiments: NTF FK MCN. Performed the experiments: NTF JAH LN SAS LS AGa CL KV MSS. Analyzed the data: NTF JAH FK JFS MSS. Contributed reagents/materials/analysis tools: LS RWS JPM AGo BDW. Wrote the paper: NTF PJB LS SAS RWS JPM FK MCN.Attached Files
Published - journal.ppat.1005238.pdf
Supplemental Material - journal.ppat.1005238.s001.PDF
Supplemental Material - journal.ppat.1005238.s002.PDF
Supplemental Material - journal.ppat.1005238.s003.PDF
Supplemental Material - journal.ppat.1005238.s004.PDF
Supplemental Material - journal.ppat.1005238.s005.XLSX
Supplemental Material - journal.ppat.1005238.s006.XLSX
Supplemental Material - journal.ppat.1005238.s007.XLSX
Supplemental Material - journal.ppat.1005238.s008.XLSX
Supplemental Material - journal.ppat.1005238.s009.XLSX
Supplemental Material - journal.ppat.1005238.s010.XLSX
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Additional details
- PMCID
- PMC4627763
- Eprint ID
- 61994
- Resolver ID
- CaltechAUTHORS:20151109-110339907
- Rockefeller University
- NIH
- 1 P01 AI100148
- NIH
- AI110657
- Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery
- OPP1032144
- Howard Hughes Medical Institute (HHMI)
- Created
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2015-11-09Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field