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

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

doi:10.1016/j.immuni.2021.12.003

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

Journal Article · 05 January 2022 · Immunity

DOI: https://doi.org/10.1016/j.immuni.2021.12.003 · OSTI ID:1981642

^[1];

^[2]; Labuhn, Maurice ^[3]; Dold, Leona ^[4]; Schoofs, Till ^[1];

^[1]; Ercanoglu, Meryem S. ^[1];

^[1];

^[5]; Vanshylla, Kanika ^[1]; Langhans, Bettina ^[6]; Janicki, Hanna ^[1]; Ströh, Luisa J. ^[7]; Knops, Elena ^[1]; Nierhoff, Dirk ^[1]; Spengler, Ulrich ^[6]; Kaiser, Rolf ^[8]; Bjorkman, Pamela J. ^[9];

^[10] more »

University of Cologne (Germany)
Univ. of Tubingen (Germany)
Centre for Experimental and Clinical Infection Research (Germany)
University of Cologne (Germany); University Hospital of Bonn (Germany); German Center for Infection Research (DZIF) (Germany)
University of Cologne (Germany); German Center for Infection Research (DZIF) (Germany)
University Hospital of Bonn (Germany); German Center for Infection Research (DZIF) (Germany)
Hannover Medical School (Germany)
German Center for Infection Research (DZIF) (Germany); University of Cologne (Germany)
California Institute of Technology (CalTech), Pasadena, CA (United States)
Hannover Medical School (Germany); University of Lubeck (Germany); Centre for Structural Systems Biology (CSSB) (Germany); German Center for Infection Research (DZIF) (Germany)
Centre for Experimental and Clinical Infection Research (Germany); Hannover Medical School (Germany); German Center for Infection Research (DZIF) (Germany)

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. Finally, our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.

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Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1981642

Journal Information:: Immunity, Journal Name: Immunity Journal Issue: 2 Vol. 55; ISSN 1074-7613

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: English

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Additional file 1 of Determination of the frequency of individuals with broadly cross-reactive neutralizing antibodies against PRRSV in the sow population under field conditions Plaza-Soriano, Ángeles; Martínez-Lobo, Francisco Javier; Garza-Moreno, Laura figshare https://doi.org/10.6084/m9.figshare.26211444	image	January 2024

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60 APPLIED LIFE SCIENCES
HCV
VH1-69
elite neutralizer
hepatitis C virus
machine learning
monoclonal antibody
neutralizing antibody
single B cell analysis
somatic mutation

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

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References (77)

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