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Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals

Bozhanova, Nina G. and Flyak, Andrew I. and Brown, Benjamin P. and Ruiz, Stormy E. and Salas, Jordan and Rho, Semi and Bombardi, Robin G. and Myers, Luke and Soto, Cinque and Bailey, Justin R. and Crowe, James E., Jr. and Bjorkman, Pamela J. and Meiler, Jens (2022) Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals. Nature Communications, 13 . Art. No. 3178. ISSN 2041-1723. PMCID PMC9177688. doi:10.1038/s41467-022-30865-9. https://resolver.caltech.edu/CaltechAUTHORS:20220614-221965000

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Abstract

Despite recent success in hepatitis C virus (HCV) treatment using antivirals, an HCV vaccine is still needed to prevent reinfections in treated patients, to avert the emergence of drug-resistant strains, and to provide protection for people with no access to the antiviral therapeutics. The early production of broadly neutralizing antibodies (bNAbs) associates with HCV clearance. Several potent bNAbs bind a conserved HCV glycoprotein E2 epitope using an unusual heavy chain complementarity determining region 3 (HCDR3) containing an intra-loop disulfide bond. Isolation of additional structurally-homologous bNAbs would facilitate the recognition of key determinants of such bNAbs and guide rational vaccine design. Here we report the identification of new antibodies containing an HCDR3 disulfide bond motif using computational screening with the Rosetta software. Using the newly-discovered and already-known members of this antibody family, we review the required HCDR3 amino acid composition and propose determinants for the bent versus straight HCDR3 loop conformation observed in these antibodies.


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https://www.ncbi.nlm.nih.gov/bioproject/PRJNA813433/Related ItemData
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ORCID:
AuthorORCID
Bozhanova, Nina G.0000-0002-2164-5698
Flyak, Andrew I.0000-0002-8722-479X
Brown, Benjamin P.0000-0001-5296-087X
Ruiz, Stormy E.0000-0003-0892-9626
Salas, Jordan0000-0002-9000-4843
Rho, Semi0000-0003-0531-2030
Bombardi, Robin G.0000-0002-6845-9075
Myers, Luke0000-0003-1132-2550
Soto, Cinque0000-0002-3997-6217
Bailey, Justin R.0000-0001-5704-3130
Crowe, James E., Jr.0000-0002-0049-1079
Bjorkman, Pamela J.0000-0002-2277-3990
Meiler, Jens0000-0001-8945-193X
Additional Information:© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 22 March 2021. Accepted 20 May 2022. Published 08 June 2022. We thank the Caltech Protein Expression Center (Dr. Jost Vielmetter, director) for help with protein expression. Structural studies were assisted by the Caltech Molecular Observatory (Dr. Jens Kaiser, director). This research was supported by the National Institutes of Health grant R01 AI127469 (to J.R.B. and P.J.B.), grants U01 AI150739 and R01 AI141661 (to J.M. and J.E.C.), grant U19 AI159822 (to J.R.B. and P.J.B.), and U.S. 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 under 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. Contributions: N.G.B., A.I.F., B.P.B., J.R.B., J.E.C., P.J.B., and J.M. designed the study; N.G.B. and B.P.B. performed the computational analysis; A.I.F., S.E.R., J.S., and S.R. performed wetlab experiments; R.G.B. prepared and sequenced Ab libraries; L.M. and C.S. processed sequencing data; J.R.B., J.E.C., P.J.B., and J.M. supervised the project and provided funding; N.G.B. and A.I.F. wrote the first draft of the manuscript; all authors read and edited the manuscript. Data availability: The crystal structures reported in this paper has been deposited to the Protein Data Bank under accession numbers 7U0B and 7U0C. Other structures used in this study are available in the Protein Data Bank under accession numbers 2FB4 (Kol)59, 6C6Z (CDC2-C2)60, 5BV7 (27C3)61, 4NZU (13PL)62, 3EYF (8F9)63, 6IEA (R13)64, 6MED (HEPC3)25, 5V7U (dmCBTAU)65, 6VBQ (DH822)66, 6BKB (AR3A)21, 6MEF (AR3C)25, 6Q19 (652Int)67, 6WO4 (HC11)23, 6URH (AR3X)22, 4PTU (C05)68, 6APC (ADI)69, 5IG7 (1002-1E01)70, 6MEE (HEPC74)70, 6BLI (CB002.5)71, 6Q1J (H2227)67, 6PBV (Fab668)72, 6UOE (3–25)73, 6Q1G (H1244)67, 6Q0E (652UCA)67, 4XAK (m336)32. NGS data for Ab libraries were deposited to the Sequence Read Archive under accession number PRJNA813433. Rosetta Ab models as well as coordinate and restart files for all MD trajectories can be accessed from GitHub at https://github.com/meilerlab/HEPC3. Source data are provided with this paper. Further information on research design is available in the Nature Research Reporting Summary linked to this article. Competing interests: J.E.C. has served as a consultant for Luna Innovations, Merck, and GlaxoSmithKline, is a member of the Scientific Advisory Board of Meissa Vaccines, and is the Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received unrelated sponsored research agreements from Takeda Pharmaceuticals, IDBiologics and AstraZeneca. Some human monoclonal antibodies in this paper are described in International Patent Application No. PCT/US2018/029315 entitled “Broadly Neutralizing Antibodies Against Hepatitis C Virus”, filed by Vanderbilt University on behalf of Vanderbilt and Johns Hopkins University; JEC, AIF and JRB are listed as inventors. The remaining authors declare no competing interests. Peer review information: Nature Communications thanks Matthew Raybould and the other, anonymous reviewers for their contribution to the peer review of this work.
Funders:
Funding AgencyGrant Number
NIHR01 AI127469
NIHU01 AI150739
NIHR01 AI141661
NIHU19 AI159822
NIHK99 AI153465
Gordon and Betty Moore FoundationUNSPECIFIED
Department of Energy (DOE)DE-AC02-76SF00515
NIHP41GM103393
PubMed Central ID:PMC9177688
DOI:10.1038/s41467-022-30865-9
Record Number:CaltechAUTHORS:20220614-221965000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220614-221965000
Official Citation:Bozhanova, N.G., Flyak, A.I., Brown, B.P. et al. Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals. Nat Commun 13, 3178 (2022). https://doi.org/10.1038/s41467-022-30865-9
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115139
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:15 Jun 2022 14:48
Last Modified:15 Jun 2022 14:48

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