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Published June 18, 2019 | Published + Supplemental Material
Journal Article Open

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448_(gp120) glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

Additional Information

© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 16 January 2019, Revised 20 March 2019, Accepted 26 April 2019, Available online 21 May 2019. We thank members of the Bjorkman, Nussenzweig, and Klein labs for helpful discussions. We also thank Gaëlle Breton and Kristie Gordon for help with flow cytometry sorting, and Anna Gazumyan, Hanna Janicki, Carola Ruping, Kanika Vanshylla, and Daniela Weiland for technical assistance. BG505 SOSIP.664-Avi, BG505 SOSIP.664-His, the CHO cell line expressing the B41 SOSIP Trimer, and the BG505.T332N gp160 expression plasmid were kind gifts of Albert Cupo, John P. Moore, and Rogier W. Sanders. The two protocols that subject 27845 was enrolled in were funded by the NIH (UM1 AI068618 and P01 AI057005) and the Bill and Melinda Gates Foundation. Structural studies were assisted by the Caltech Molecular Observatory (Dr. Jens Kaiser, director) and the Biological and Cryogenic Transmission Electron Microscopy Center at Caltech (Drs. Andrey Malyutin and Songye Chen, directors). Part of the cryo-EM work was performed at the Cold Spring Harbor Laboratories Course of Cryo-EM Methods with help from Drs. Gabriel Lander, Melanie Ohi, Matthjin Vos, David Veesler, and Justin Kollman. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory and electron microscopy. This work was supported by the National Institute of Allergy and Infectious Diseases of the NIH (HIVRAD P01 AI100148 to P.J.B. and M.C.N. and R01 AI131722 to I.S.G.); the NIH (P50 GM082545-06 to P.J.B.); the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (OPP1124068 to M.C.N. and P.J.B. and 1146996 to M.S.S.); the NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) (1UM1 AI100663-01 to M.C.N.); the European Research Council (ERC-StG639961 to F.K.); the German Center for Infection Research (DZIF) (to F.K.); and in part by the intramural research program of the Vaccine Research Center, NIAID/NIH (to J.R.M.). T.S. was supported by the Ernst Jung Career Advancement Award for Medical Research, the National Center for Advancing Translational Sciences (NCATS, NIH Clinical and Translational Science Award [CTSA] program, UL1 TR001866), and the DZIF (TI 07.002). C.O.B was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. P.S. and H.G. were supported by the DZIF. M.C.N. is a HHMI investigator. Author Contributions: T.S., C.O.B., N.A.D.-R., J.R.M., F.K., M.C.N., and P.J.B. conceived the study and analyzed data. J.C. and M.J.M. supervised clinical protocols and provided samples from donor 27845. L.N. isolated immunoglobulin for analysis. I.S.G. carried out neutralization fingerprinting. N.A.D.-R. and T.S. performed B cell microcultures. R.T.B. carried out microculture neutralization analysis. J.G. and T.S. performed single B cell bait-sorting and B cell cloning. M.S.S. performed large panel neutralization testing. A.P.W. computationally analyzed neutralization data. T.S. performed ELISAs and generated pseudoviruses for site mutant analysis. P.S. performed neutralization testing on site mutants, and some global panel testing of family members. N.S.-T. and C.O.B. generated the Fab structure. C.O.B. generated and analyzed the cryo-EM structure of the SF12-B41 complex. Y.E.L. and T.S. performed polyreactivity and autoreactivity assays. T.S. and H.G. performed mouse experiments. F.B. humanized mice and screened them for humanization. F.K. designed and supervised mouse experiments. T.S., C.O.B., M.C.N., and P.J.B. wrote the manuscript with contributions from other authors. Declaration of Interests: There are patents on 3BNC117 and 10-1074 on which M.C.N. and P.J.B. are inventors.

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