CaltechAUTHORS
  A Caltech Library Service

Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization

Weber, Timm and Potthoff, Julian and Bizu, Sven and Labuhn, Maurice and Dold, Leona and Schoofs, Till and Horning, Marcel and Ercanoglu, Meryem S. and Kreer, Christoph and Gieselmann, Lutz and Vanshylla, Kanika and Langhans, Bettina and Janicki, Hanna and Ströh, Luisa J. and Knops, Elena and Nierhoff, Dirk and Spengler, Ulrich and Kaiser, Rolf and Bjorkman, Pamela J. and Krey, Thomas and Bankwitz, Dorothea and Pfeifer, Nico and Pietschmann, Thomas and Flyak, Andrew I. and Klein, Florian (2022) Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization. Immunity, 55 (2). pp. 341-354. ISSN 1074-7613. doi:10.1016/j.immuni.2021.12.003. https://resolver.caltech.edu/CaltechAUTHORS:20220112-695042490

This is the latest version of this item.

[img] PDF (Document S1. Figures S1–S5 and Tables S1, S2, S4, and S5) - Supplemental Material
See Usage Policy.

5MB
[img] MS Excel (Table S3. Isolated HCV antibodies, related to Figure 3) - Supplemental Material
See Usage Policy.

33kB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20220112-695042490

Abstract

The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%–5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.immuni.2021.12.003DOIArticle
ORCID:
AuthorORCID
Weber, Timm0000-0003-2079-842X
Potthoff, Julian0000-0003-3243-1115
Bizu, Sven0000-0003-4839-2472
Dold, Leona0000-0002-7677-3347
Schoofs, Till0000-0002-3584-8736
Horning, Marcel0000-0003-1468-4645
Ercanoglu, Meryem S.0000-0001-8026-8565
Kreer, Christoph0000-0002-9140-9850
Gieselmann, Lutz0000-0003-3699-3318
Vanshylla, Kanika0000-0003-4552-9170
Langhans, Bettina0000-0001-7733-1092
Ströh, Luisa J.0000-0002-2781-2303
Knops, Elena0000-0001-7398-3026
Nierhoff, Dirk0000-0001-7297-2675
Spengler, Ulrich0000-0002-8746-2413
Kaiser, Rolf0000-0002-3704-5785
Bjorkman, Pamela J.0000-0002-2277-3990
Krey, Thomas0000-0002-4548-7241
Bankwitz, Dorothea0000-0002-8185-3202
Pfeifer, Nico0000-0002-4647-8566
Pietschmann, Thomas0000-0001-6789-4422
Flyak, Andrew I.0000-0002-8722-479X
Klein, Florian0000-0003-1376-1792
Additional Information:© 2021 Elsevier. Received 16 July 2021, Revised 21 October 2021, Accepted 6 December 2021, Available online 5 January 2022. We thank all study participants who devoted time to our research; members of the Klein, Pietschmann, Pfeifer, Krey, and Bjorkman Laboratories for continuous support and helpful discussions, Maike Schlotz and Carola Ruping for help with sample processing, and Henning Gruell for valuable discussions. We thank the Caltech Protein Expression Center for help with protein expression and the Caltech Molecular Observatory for assistance with structural studies. This work was funded by grants from the European Research Council (ERC-STG-639961 to F.K.), the German Center for Infection Research (DZIF TTU 05.817 and TTU 05.821 to F.K., T.P., T.K., and T.W.) and the German Research Foundation (DFG) (CRC 1310 to F.K.). T.P. and T.K. are funded by the DFG under Germany’s Excellence Strategy (EXC 2155 “RESIST”—project ID 39087428). This research was also supported by the U.S. National Institutes of Health (NIH) (NIH grant R01 AI127469 to P.J.B.) and (NIH grant K99 AI153465 to A.I.F.) (content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH) and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences (contract no DE-AC02-76SF00515). The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by NIHGMS (P41GM103393). Author contributions: Conceptualization, T.W., T.P., A.I.F., and F.K.; methodology, T.W., J.P., S.B., M.L., L.D., T.S., M.H., M.S.E., C.K., L.G., K.V., P.J.B., T.K., D.B., N.P., T.P., A.I.F., and F.K.; investigation, T.W., J.P., S.B., M.L., L.D., T.S., M.H., M.S.E., C.K., L.G., K.V., H.J., D.B., and A.I.F.; software, S.B., C.K., and N.P.; formal analysis, T.W., J.P., L.D., T.S., M.H., C.K., N.P., A.I.F., and F.K.; resources, B.L., L.S., E.K., D.N., U.S., R.K., P.J.B., T.K., T.P., and F.K.; writing–original draft, T.W., J.P., A.I.F., and F.K.; supervision, P.J.B., T.K., N.P., T.P., and F.K. Declaration of interests: Reported antibodies are in the process of being patented. Data and code availability: Nucleotide sequences of all antibodies have been deposited at Genbank. NGS data have been deposited at the Sequence Read Archive (SRA). Coordinates for atomic models have been deposited at the Protein Data Bank (PDB). The data are publicly available as of the date of publication and accession numbers are listed in the key resources table. All original code has been deposited at Zenodo and is publicly available as of the date of publication. The Digital Object Identifier (DOI) is listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Funders:
Funding AgencyGrant Number
European Research Council (ERC)639961
German Center for Infection Research (DZIF)TTU 05.817
German Center for Infection Research (DZIF)TTU 05.821
Deutsche Forschungsgemeinschaft (DFG)CRC 1310
Deutsche Forschungsgemeinschaft (DFG)EXC 2155
NIHR01 AI127469
NIHK99 AI153465
Gordon and Betty Moore FoundationUNSPECIFIED
Department of Energy (DOE)DE-AC02-76SF00515
NIHP41GM103393
Subject Keywords:hepatitis C virus; HCV; neutralizing antibody; monoclonal antibody; single B cell analysis; elite neutralizer; VH1-69; somatic mutation; machine learning
Issue or Number:2
DOI:10.1016/j.immuni.2021.12.003
Record Number:CaltechAUTHORS:20220112-695042490
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220112-695042490
Official Citation:Timm Weber, Julian Potthoff, Sven Bizu, Maurce Labuhn, Leona Dold, Till Schoofs, Marcel Horning, Meryem S. Ercanoglu, Christoph Kreer, Lutz Gieselmann, Kanika Vanshylla, Bettina Langhans, Hanna Janicki, Luisa J. Ströh, Elena Knops, Dirk Nierhoff, Ulrich Spengler, Rolf Kaiser, Pamela J. Bjorkman, Thomas Krey, Dorothea Bankwitz, Nico Pfeifer, Thomas Pietschmann, Andrew I. Flyak, Florian Klein, Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization, Immunity, Volume 55, Issue 2, 2022, Pages 341-354.e7, ISSN 1074-7613, https://doi.org/10.1016/j.immuni.2021.12.003.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112843
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Jan 2022 11:40
Last Modified:15 Mar 2022 16:48

Available Versions of this Item

  • Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization. (deposited 12 Jan 2022 11:40) [Currently Displayed]

Commentary/Response Threads

  • Weber, Timm and Potthoff, Julian and Bizu, Sven and Labuhn, Maurice and Dold, Leona and Schoofs, Till and Horning, Marcel and Ercanoglu, Meryem S. and Kreer, Christoph and Gieselmann, Lutz and Vanshylla, Kanika and Langhans, Bettina and Janicki, Hanna and Ströh, Luisa J. and Knops, Elena and Nierhoff, Dirk and Spengler, Ulrich and Kaiser, Rolf and Bjorkman, Pamela J. and Krey, Thomas and Bankwitz, Dorothea and Pfeifer, Nico and Pietschmann, Thomas and Flyak, Andrew I. and Klein, Florian Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization. (deposited 12 Jan 2022 11:40) [Currently Displayed]

Repository Staff Only: item control page