Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller
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-1_(YU2)–infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection.
Additional Information
© 2017 American Association for the Advancement of Science. Submitted 22 July 2016; Resubmitted 14 October 2016; Accepted 8 December 2016; Published 18 January 2017. 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. 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.Attached Files
Accepted Version - nihms862638.pdf
Supplemental Material - aal2144_SM.pdf
Supplemental Material - aal2144_Tables_S1_to_S5.zip
Files
Additional details
- PMCID
- PMC5467220
- Eprint ID
- 73617
- Resolver ID
- CaltechAUTHORS:20170123-102509140
- Robertson Foundation
- Rockefeller University
- OPP1033115
- Bill and Melinda Gates Foundation
- UM1 AI 100663
- NIH
- 1 P01 AI100148
- NIH
- 2 P50 GM082545-06
- NIH
- Gordon and Betty Moore Foundation
- OPP1032144
- Bill and Melinda Gates Foundation
- F12-CT-214
- California HIV/AIDS Research Program
- Howard Hughes Medical Institute (HHMI)
- Created
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2017-01-26Created from EPrint's datestamp field
- Updated
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2022-04-06Created from EPrint's last_modified field