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Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Schommers, Philipp and Gruell, Henning and Abernathy, Morgan E. and Tran, My-Kim and Dingens, Adam S. and Gristick, Harry B. and Barnes, Christopher O. and Schoofs, Till and Schlotz, Maike and Vanshylla, Kanika and Kreer, Christoph and Weiland, Daniela and Holtick, Udo and Scheid, Christof and Valter, Markus M. and van Gils, Marit J. and Sanders, Rogier W. and Vehreschild, Jörg J. and Cornely, Oliver A. and Lehmann, Clara and Fätkenheuer, Gerd and Seaman, Michael S. and Bloom, Jesse D. and Bjorkman, Pamela J. and Klein, Florian (2020) Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody. Cell, 180 (3). pp. 471-489. ISSN 0092-8674. PMCID PMC7042716. https://resolver.caltech.edu/CaltechAUTHORS:20200130-110348875

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2020.01.010DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042716PubMed CentralArticle
ORCID:
AuthorORCID
Bloom, Jesse D.0000-0003-1267-3408
Bjorkman, Pamela J.0000-0002-2277-3990
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.
Funders:
Funding AgencyGrant Number
Helmholtz Centre for Infection ResearchUNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
Hans‐Böckler FoundationUNSPECIFIED
University of CologneUNSPECIFIED
Ernst Jung Career Advancement Award for Medical ResearchUNSPECIFIED
Federal Joint Committee01VSF18036
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Bill and Melinda Gates FoundationOPP1146996
NIHR01 AI140891
NIHP01 AI110657
NIHP01 AI100148
NIHP50 GM082545-06
Deutsche Forschungsgemeinschaft (DFG)CRC 1279
Deutsche Forschungsgemeinschaft (DFG)CRC 1310
Deutsche Forschungsgemeinschaft (DFG)KL2389/2-1
European Research Council (ERC)639961
Subject Keywords:HIV-1; broadly neutralizing antibodies; CD4 binding site; escape mutations; immunotherapy; cryogenic electron microscopy; deep mutational scanning; mutational antigenic profiling; HIV-1 escape restriction; humanized mice
Issue or Number:3
PubMed Central ID:PMC7042716
Record Number:CaltechAUTHORS:20200130-110348875
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200130-110348875
Official Citation:Philipp Schommers, Henning Gruell, Morgan E. Abernathy, My-Kim Tran, Adam S. Dingens, Harry B. Gristick, Christopher O. Barnes, Till Schoofs, Maike Schlotz, Kanika Vanshylla, Christoph Kreer, Daniela Weiland, Udo Holtick, Christof Scheid, Markus M. Valter, Marit J. van Gils, Rogier W. Sanders, Jörg J. Vehreschild, Oliver A. Cornely, Clara Lehmann, Gerd Fätkenheuer, Michael S. Seaman, Jesse D. Bloom, Pamela J. Bjorkman, Florian Klein, Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody, Cell, Volume 180, Issue 3, 2020, Pages 471-489.e22, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2020.01.010. (http://www.sciencedirect.com/science/article/pii/S009286742030057X)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101003
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Jan 2020 19:18
Last Modified:06 Mar 2020 15:55

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