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A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo

Freund, Natalia T. and Horwitz, Joshua A. and Nogueira, Lilian and Sievers, Stuart A. and Scharf, Louise and Scheid, Johannes F. and Gazumyan, Anna and Liu, Cassie and Velinzon, Klara and Goldenthal, Ariel and Sanders, Rogier W. and Moore, John P. and Bjorkman, Pamela J. and Seaman, Michael S. and Walker, Bruce D. and Klein, Florian and Nussenzweig, Michel C. (2015) A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo. PLoS Pathogens, 11 (10). Art. No. e1005238. ISSN 1553-7366. PMCID PMC4627763. https://resolver.caltech.edu/CaltechAUTHORS:20151109-110339907

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[img] PDF (S1 Fig. Number of mutations in V-region in the 2CC core-sorted antibodies) - Supplemental Material
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[img] PDF (S2 Fig. Binding of 179NC75 and its variants to soluble Env proteins in ELISA) - Supplemental Material
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[img] PDF (S3 Fig. SPR binding studies) - Supplemental Material
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[img] PDF (S4 Fig. Binding of 179NC75 and its variants to BG505 SOSIP,664-D7324 trimers in ELISA) - Supplemental Material
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[img] MS Excel (S1 Table. IC50 values for purified IgG from EB179 tested in TZM.bl assays) - Supplemental Material
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[img] MS Excel (S2 Table. Expressed antibodies from 2CC core-sorted B cells) - Supplemental Material
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[img] MS Excel (S3 Table. Neutralizing activity of 179NC75) - Supplemental Material
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[img] MS Excel (S4 Table. Summary of IC50 and IC80 values for the 120 virus test panel) - Supplemental Material
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[img] MS Excel (S5 Table. IC50 values of 179NC75, 3BNC117, VRC01 and HJ16 tested against 53 common viruses) - Supplemental Material
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[img] MS Excel (S6 Table. Comparison of 179NC75, 3BNC60 and 8ANC195 binding to BG505 SOSIP.664 containing a mixture of complex and high-mannose or exclusively high-mannose glycans) - Supplemental Material
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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 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.ppat.1005238DOIArticle
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005238PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627763/PubMed CentralArticle
ORCID:
AuthorORCID
Freund, Natalia T.0000-0002-5386-502X
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
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.
Funders:
Funding AgencyGrant Number
Rockefeller UniversityUNSPECIFIED
NIH1 P01 AI100148
NIHAI110657
Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine DiscoveryOPP1032144
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC4627763
Record Number:CaltechAUTHORS:20151109-110339907
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20151109-110339907
Official Citation:Freund NT, Horwitz JA, Nogueira L, Sievers SA, Scharf L, Scheid JF, et al. (2015) A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo. PLoS Pathog 11(10): e1005238. doi:10.1371/journal.ppat.1005238
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:61994
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Nov 2015 19:33
Last Modified:03 Oct 2019 09:14

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