Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody
- Creators
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Schommers, Philipp
- Gruell, Henning
- Abernathy, Morgan E.
- Tran, My-Kim
- Dingens, Adam S.
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Gristick, Harry B.
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Barnes, Christopher O.
- Schoofs, Till
- Schlotz, Maike
- Vanshylla, Kanika
- Kreer, Christoph
- Weiland, Daniela
- Holtick, Udo
- Scheid, Christof
- Valter, Markus M.
- van Gils, Marit J.
- Sanders, Rogier W.
- Vehreschild, Jörg J.
- Cornely, Oliver A.
- Lehmann, Clara
- Fätkenheuer, Gerd
- Seaman, Michael S.
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Bloom, Jesse D.
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Bjorkman, Pamela J.
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Klein, Florian
Abstract
Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V_H1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC₅₀ = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505_(SOSIP.664) Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
Additional Information
© 2020 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 30 September 2019, Revised 5 December 2019, Accepted 6 January 2020, Available online 30 January 2020. We thank all study participants who devoted time to our research; members of the Klein and Bjorkman laboratories for helpful discussion; A.P. West, Jr. for sequence analysis; M.S. Ercanoglu and K. Jain for cell sorting; K. Jain, H. Janicki, C. Ruping, and J. Schmatz for antibody production and sample processing; S. Arzberger and F. Bach for generating humanized mice; A. Adhikari, R. Duerr, S. Esser, O. Geisenberger, C. Geldmacher, M. Hölscher, A. Kroidl, T. Kümmerle, K. Römer, S. Scholten, C. Stephan, H. Streeck, T. Wolf, C. Wyen, and S. Zolla-Pazner for contributing to the screening cohort; J.P. Moore and A. Cupo for the stable CHO cell line expressing BG505_(SOSIP.664); E. Heger for SupT1-R5 cells; T.Y. Oliveira for providing sequence assembly software; I.S. Georgiev for neutralizing fingerprint analysis; N.A. Doria-Rose for providing RSC3; L. Stamatatos for providing eOD-GT8; Z. Yang and A. Malyutin for assistance with cryo-EM data collection; the Cologne Center for Genomics for sequencing support; and the staff of the Animal Care Facility Weyertal at the University of Cologne. The panel of global HIV-1 clones was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH (ARP) from David Montefiori (deCamp et al., 2014), and TZM-bl cells were obtained through the ARP from John C. Kappes and Xiaoyun Wu (Platt et al., 1998). Cryo-EM was done at the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. Support was provided by fellowships from the German Center for Infection Research (DZIF) (to P.S. and H.G.), the Graduate Research Fellowship Program (GRFP) of the National Science Foundation (NSF) (to M.E.A), scholarships from the Hans‐Böckler Foundation and the Köln Fortune Program of the Faculty of Medicine of the University of Cologne (to M.-K.T), the Ernst Jung Career Advancement Award for Medical Research (to T.S.), and the Federal Joint Committee (G-BA) (01VSF18036 to C.L.). J.D.B. is an Investigator of the Howard Hughes Medical Institute. This work was supported by Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant OPP1146996 (to M.S.S.); National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) grants R01 AI140891 (to J.D.B.), HIVRAD P01 AI110657 (to R.W.S.), and HIVRAD P01 AI100148 (to P.J.B.); NIH grant P50 GM082545-06 (to P.J.B.); and grants from the German Center for Infection Research (DZIF; to F.K.), the German Research Foundation (CRC 1279 and CRC 1310 to F.K.), the DFG Heisenberg Program (KL2389/2-1 to F.K.), and the European Research Council (ERC-StG639961 to F.K.). Author Contributions: Conceptualization, F.K; Methodology, P.S., H.G., M.E.A., A.S.D., J.D.B., P.J.B., and F.K.; Investigation, P.S., H.G., M.E.A., M.-K.T., A.S.D., H.B.G., C.O.B., T.S., M.S., K.V., C.K., and M.S.S.; Resources, K.V., D.W., U.H., C.S., M.M.V., M.J.v.G., R.W.S., J.J.V., O.A.C., C.L., and G.F.; Software, A.S.D. and C.K.; Formal Analysis, P.S., H.G., A.S.D., C.K., and M.S.S.; Writing – Original Draft, P.S., H.G., M.E.A., H.B.G., P.J.B., and F.K.; Writing – Review & Editing, A.S.D., T.S., K.V., C.K., R.W.S., and J.D.B.; Visualization, P.S., H.G., M.E.A., A.S.D., and F.K.; Supervision, J.D.B., P.J.B., and F.K.; Funding Acquisition, P.J.B. and F.K. Declaration of Interests: A patent application encompassing aspects of this work has been filed by the University of Cologne, listing P.S., H.G., and F.K. as inventors.Attached Files
Published - 1-s2.0-S009286742030057X-main.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc1.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc2.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc3.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc4.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc5.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc6.pdf
Supplemental Material - 1-s2.0-S009286742030057X-mmc7.pdf
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Additional details
- PMCID
- PMC7042716
- Eprint ID
- 101003
- Resolver ID
- CaltechAUTHORS:20200130-110348875
- Helmholtz Centre for Infection Research
- NSF Graduate Research Fellowship
- Hans‐Böckler Foundation
- University of Cologne
- Ernst Jung Career Advancement Award for Medical Research
- 01VSF18036
- Federal Joint Committee
- Howard Hughes Medical Institute (HHMI)
- OPP1146996
- Bill and Melinda Gates Foundation
- R01 AI140891
- NIH
- P01 AI110657
- NIH
- P01 AI100148
- NIH
- P50 GM082545-06
- NIH
- CRC 1279
- Deutsche Forschungsgemeinschaft (DFG)
- CRC 1310
- Deutsche Forschungsgemeinschaft (DFG)
- KL2389/2-1
- Deutsche Forschungsgemeinschaft (DFG)
- 639961
- European Research Council (ERC)
- Created
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2020-01-30Created from EPrint's datestamp field
- Updated
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2022-02-16Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering