Signatures of VH1-69-derived hepatitis C virus neutralizing antibody precursors defined by binding to envelope glycoproteins

Joan Capella-Pujol, Marlon Gast, Laura Radić, Ian Zon, Ana Chumbe, Sylvie Koekkoek, Wouter Olijhoek, Janke Schinkel, Marit J. Gils, Rogier W. Sanders () and Kwinten Sliepen ()
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Joan Capella-Pujol: University of Amsterdam
Marlon Gast: University of Amsterdam
Laura Radić: University of Amsterdam
Ian Zon: University of Amsterdam
Ana Chumbe: University of Amsterdam
Sylvie Koekkoek: University of Amsterdam
Wouter Olijhoek: University of Amsterdam
Janke Schinkel: University of Amsterdam
Marit J. Gils: University of Amsterdam
Rogier W. Sanders: University of Amsterdam
Kwinten Sliepen: University of Amsterdam

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract An effective preventive vaccine for hepatitis C virus (HCV) remains a major unmet need. Antigenic region 3 (AR3) on the E1E2 envelope glycoprotein complex overlaps with the CD81 receptor binding site and represents an important epitope for broadly neutralizing antibodies (bNAbs) and is therefore important for HCV vaccine design. Most AR3 bNAbs utilize the VH1-69 gene and share structural features that define the AR3C-class of HCV bNAbs. In this work, we identify recombinant HCV glycoproteins based on a permuted E2E1 trimer design that bind to the inferred VH1-69 germline precursors of AR3C-class bNAbs. When presented on nanoparticles, these recombinant E2E1 glycoproteins efficiently activate B cells expressing inferred germline AR3C-class bNAb precursors as B cell receptors. Furthermore, we identify critical signatures in three AR3C-class bNAbs that represent two subclasses of AR3C-class bNAbs that will allow refined protein design. These results provide a framework for germline-targeting vaccine design strategies against HCV.

Date: 2023
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DOI: 10.1038/s41467-023-39690-0

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