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Research Article
HIV

Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller

Natalia T. Freund, Haoqing Wang, Louise Scharf, Lilian Nogueira, Joshua A. Horwitz, Yotam Bar-On, Jovana Golijanin, Stuart A. Sievers, Devin Sok, Hui Cai, Julio C. Cesar Lorenzi, Ariel Halper-Stromberg, Ildiko Toth, Alicja Piechocka-Trocha, Harry B. Gristick, Marit J. van Gils, Rogier W. Sanders, Lai-Xi Wang, Michael S. Seaman, Dennis R. Burton, Anna Gazumyan, Bruce D. Walker, Anthony P. West Jr, Pamela J. Bjorkman, and Michel C. Nussenzweig [email protected]
Science Translational Medicine • 18 Jan 2017 • Vol 9, Issue 373 • DOI: 10.1126/scitranslmed.aal2144
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Antibodies can hold HIV-1 at an impasse

Neutralizing antibodies put selective pressure on pathogens to mutate and escape from immune detection, which is one of the reasons why HIV-1 infection is difficult to contain. In this issue, Freund et al. studied samples spanning almost a decade from an individual who naturally controls HIV-1 infection without progressing to AIDS. They discovered three potent antibodies coexisting with viral strains that were sensitive to antibody neutralization, indicating that these antibodies may be contributing to viral control. These antibodies were also able to prevent HIV-1 viremia in humanized mice, demonstrating that the antibodies may be beneficial as passive immunotherapy for infected individuals.

Abstract

Some HIV-1–infected patients develop broad and potent HIV-1 neutralizing antibodies (bNAbs) that when passively transferred to mice or macaques can treat or prevent infection. However, bNAbs typically fail to neutralize coexisting autologous viruses due to antibody-mediated selection against sensitive viral strains. We describe an HIV-1 controller expressing HLA-B57*01 and HLA-B27*05 who maintained low viral loads for 30 years after infection and developed broad and potent serologic activity against HIV-1. Neutralization was attributed to three different bNAbs targeting nonoverlapping sites on the HIV-1 envelope trimer (Env). One of the three, BG18, an antibody directed against the glycan-V3 portion of Env, is the most potent member of this class reported to date and, as revealed by crystallography and electron microscopy, recognizes HIV-1 Env in a manner that is distinct from other bNAbs in this class. Single-genome sequencing of HIV-1 from serum samples obtained over a period of 9 years showed a diverse group of circulating viruses, 88.5% (31 of 35) of which remained sensitive to at least one of the temporally coincident autologous bNAbs and the individual’s serum. Thus, bNAb-sensitive strains of HIV-1 coexist with potent neutralizing antibodies that target the virus and may contribute to control in this individual. When administered as a mix, the three bNAbs controlled viremia in HIV-1YU2–infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection.
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Supplementary Material

Summary

Methods
Fig. S1. Isolation of neutralizing antibody clones from donor EB354.
Fig. S2. Competitive ELISA.
Fig. S3. NC37 Fab–gp120 complex structure.
Fig. S4. Sequence comparison between BG18, PGT121, and 10-1074.
Fig. S5. BG18 antibody binding to synthetic HIV-1 V3 glycopeptides.
Fig. S6. env SGS of plasma virus from donor EB354.
Fig. S7. Viral loads in HIV-1YU2–infected and BG18- and NC37-treated humanized mice.
Fig. S8. BG8 therapy in HIV-1YU2–infected humanized mice.
Table S1. Clinical information, donor EB354 (provided in Excel).
Table S2. IC50 and IC80 values in TZM-bl assay for antibodies NC37, BG1, BG18, BG8, and 10-1074 and PGT121 against a 118-virus panel (provided in Excel).
Table S3. IC50 and IC80 values in TZM-bl assay of the 1:1:1 combination of NC37, BG1, and BG18 against a 118-virus panel (provided in Excel).
Table S4. IC50 and IC80 values in TZM-bl assay of antibodies BG8, BG18, PGT121, and 12A12 against selected HIV-1 V3 envelope mutants (provided in Excel).
Table S5. Crystallization statistics (provided in Excel).
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Information & Authors

Information

Published In

Science Translational Medicine
Volume 9 | Issue 373
January 2017

Copyright

Copyright © 2017, American Association for the Advancement of Science.

Submission history

Received: 22 July 2016
Accepted: 8 December 2016

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Acknowledgments

We thank the donor for his participation in this study. We thank Z. Jankovic for the Rockefeller University laboratory support; T. Eisenreich for help with mouse colony management; K. Velinson and N. Thomas for single-cell fluorescence-activated cell sorting; T. Schoofs for help with mice experiments and statistical analyses; G. Jensen and A. McDowall for use of EMs at Caltech; I. Nangiana, J. Vielmetter, and the Caltech Protein Expression Center for expression of proteins used for structural studies; J. P. Moore and A. Cupo for providing and developing the BG505.664 bait; and all the great members of the Nussenzweig and Bjorkman laboratories for helpful discussion and advice. Funding: This work was supported by the Robertson Foundation, the Rockefeller University, the Bill and Melinda Gates Foundation grant OPP1033115, the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Scripps grant UM1 AI 100663, the NIH HIV Vaccine Research and Design grant 1 P01 AI100148 (to M.C.N. and P.J.B.), the NIH grant 2 P50 GM082545-06 (to P.J.B.), the Molecular Observatory and EM funding at Caltech supported by the Gordon and Betty Moore Foundation, the Melinda and Bill Gates Foundation Collaboration for AIDS Vaccine Discovery grant OPP1032144 (to M.S.S.), and the California HIV/AIDS Research Program (CHRP grant F12-CT-214 to S.A.S.). Author contributions: N.T.F. planned and performed experiments, analyzed the data, and wrote the manuscript. H.W. solved the EM structure. L.S. and S.A.S. solved and analyzed crystal structures and contributed to the manuscript preparation. L.N. propagated viral cultures and helped with mouse experiments. J.A.H. propagated viral cultures, performed SGS, and contributed to the manuscript preparation. A.H.-S and Y.B.-O. helped with humanized mice experiments. J.G. and A.G. produced antibodies. J.C.C.L. performed SGS and phylogenetic and diversity analyses and helped in analyzing the data. A.P.-T. and I.T. provided the human samples and coordinated with the donor. H.B.G. refined structural structures. M.J.v.G. and R.W.S. produced and provided reagents and critically read the manuscript preparation. A.P.W. analyzed antibody sequence data. H.C. and L.-X.W. performed the glycopeptide synthesis and binding experiments. D.S. and M.S.S. performed and analyzed the neutralization assays. D.R.B. critically read and contributed to the manuscript preparation. B.D.W. provided human samples and contributed to the manuscript preparation. A.P.W. performed sequence alignment and analyses. P.J.B. planned and analyzed structural experiments and helped write the manuscript. M.C.N. planned and supervised the experiments, analyzed data, and wrote the manuscript. Competing interests: M.C.N. and B.D.W. are Howard Hughes Medical Investigators. The other authors declare that they have no competing interests.

Authors

Affiliations

Natalia T. Freund
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Haoqing Wang*
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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Louise Scharf*
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Present address: 23andMe, Mountain View, CA 94041, USA.
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Lilian Nogueira
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Joshua A. Horwitz
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Yotam Bar-On
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Jovana Golijanin
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Stuart A. Sievers
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Present address: Kite Pharma, Santa Monica, CA 90404, USA.
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Devin Sok
Department of Immunology and Microbial Science, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and International AIDS Vaccine Initiative Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.
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Hui Cai
Department of Chemistry and Biochemistry, University of Maryland, 8051 Regents Drive, College Park, MD 20742, USA.
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Julio C. Cesar Lorenzi
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Ariel Halper-Stromberg
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Ildiko Toth
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02129, USA.
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Alicja Piechocka-Trocha
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02129, USA.
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Harry B. Gristick
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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Marit J. van Gils
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
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Rogier W. Sanders
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
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Lai-Xi Wang
Department of Chemistry and Biochemistry, University of Maryland, 8051 Regents Drive, College Park, MD 20742, USA.
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Michael S. Seaman
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Dennis R. Burton
Department of Immunology and Microbial Science, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and International AIDS Vaccine Initiative Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02129, USA.
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Anna Gazumyan
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
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Bruce D. Walker
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02129, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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Anthony P. West Jr
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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Pamela J. Bjorkman
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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Michel C. Nussenzweig§ [email protected]
Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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Notes

*
These authors contributed equally to this work.
§Corresponding author. Email: [email protected]

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