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

Timm Weber; Julian Potthoff; Sven Bizu; Maurice 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

doi:10.1016/j.immuni.2021.12.003

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

Timm Weber, Julian Potthoff, Sven Bizu, Maurice 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 KreyDorothea Bankwitz, Nico Pfeifer, Thomas Pietschmann, Andrew I. Flyak, Florian Klein^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Biochemie

40 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Immunity
Jahrgang	55
Ausgabenummer	2
Seiten (von - bis)	341-354.e7
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2021.12.003
Publikationsstatus	Veröffentlicht - 08.02.2022

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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).

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10.1016/j.immuni.2021.12.003

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Weber, T., Potthoff, J., Bizu, S., Labuhn, M., Dold, L., Schoofs, T., Horning, M., Ercanoglu, M. S., Kreer, C., Gieselmann, L., Vanshylla, K., Langhans, B., Janicki, H., Ströh, L. J., Knops, E., Nierhoff, D., Spengler, U., Kaiser, R., Bjorkman, P. J., ... Klein, F. (2022). Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization. Immunity, 55(2), 341-354.e7. https://doi.org/10.1016/j.immuni.2021.12.003

@article{2a18cb3401984c3ebf1d9bdc72f96de9,

title = "Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization",

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.",

author = "Timm Weber and Julian Potthoff and Sven Bizu and Maurice Labuhn and Leona Dold and Till Schoofs and Marcel Horning and Ercanoglu, \{Meryem S.\} and Christoph Kreer and Lutz Gieselmann and Kanika Vanshylla and Bettina Langhans and Hanna Janicki and Str{\"o}h, \{Luisa J.\} and Elena Knops and Dirk Nierhoff and Ulrich Spengler and Rolf Kaiser and Bjorkman, \{Pamela J.\} and Thomas Krey and Dorothea Bankwitz and Nico Pfeifer and Thomas Pietschmann and Flyak, \{Andrew I.\} and Florian Klein",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2022",

month = feb,

day = "8",

doi = "10.1016/j.immuni.2021.12.003",

language = "English",

volume = "55",

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Weber, T, Potthoff, J, Bizu, S, Labuhn, M, Dold, L, Schoofs, T, Horning, M, Ercanoglu, MS, Kreer, C, Gieselmann, L, Vanshylla, K, Langhans, B, Janicki, H, Ströh, LJ, Knops, E, Nierhoff, D, Spengler, U, Kaiser, R, Bjorkman, PJ, Krey, T, Bankwitz, D, Pfeifer, N, Pietschmann, T, Flyak, AI & Klein, F 2022, 'Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization', Immunity, Jg. 55, Nr. 2, S. 341-354.e7. https://doi.org/10.1016/j.immuni.2021.12.003

TY - JOUR

T1 - Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization

AU - Weber, Timm

AU - Potthoff, Julian

AU - Bizu, Sven

AU - Labuhn, Maurice

AU - Dold, Leona

AU - Schoofs, Till

AU - Horning, Marcel

AU - Ercanoglu, Meryem S.

AU - Kreer, Christoph

AU - Gieselmann, Lutz

AU - Vanshylla, Kanika

AU - Langhans, Bettina

AU - Janicki, Hanna

AU - Ströh, Luisa J.

AU - Knops, Elena

AU - Nierhoff, Dirk

AU - Spengler, Ulrich

AU - Kaiser, Rolf

AU - Bjorkman, Pamela J.

AU - Krey, Thomas

AU - Bankwitz, Dorothea

AU - Pfeifer, Nico

AU - Pietschmann, Thomas

AU - Flyak, Andrew I.

AU - Klein, Florian

PY - 2022/2/8

Y1 - 2022/2/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85124015128

U2 - 10.1016/j.immuni.2021.12.003

DO - 10.1016/j.immuni.2021.12.003

M3 - Journal articles

C2 - 34990590

AN - SCOPUS:85124015128

SN - 1074-7613

VL - 55

SP - 341-354.e7

JO - Immunity

JF - Immunity

IS - 2

ER -

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

Abstract

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