@article{2d73c3dd0be745198249df9d90432af4,
title = "Signatures of VH 1-69-derived hepatitis C virus neutralizing antibody precursors defined by binding to envelope glycoproteins",
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 VH 1-69 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 VH 1-69 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.",
author = "Joan Capella-Pujol and {de Gast}, Marlon and Laura Radi{\'c} and Ian Zon and Ana Chumbe and Sylvie Koekkoek and Wouter Olijhoek and Janke Schinkel and {van Gils}, {Marit J.} and Sanders, {Rogier W.} and Kwinten Sliepen",
note = "Funding Information: We thank Tim Beaumont and Sabrina Merat (AIMM) for providing sequences and data on AT1209. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. KewaliRaman. We thank Rashmi Ravichandran and Neil P King for providing the I53-50B.4PT1 protein. This research was supported by the Fondation Dormeur, Vaduz (to R.W.S. and M.J.v.G.), an AMC Fellowship from Amsterdam UMC (M.J.v.G.), a Vici grant from the Netherlands Organization for Scientific Research (NWO) (R.W.S.), a Vidi and Aspasia grant from the NWO (grant numbers 91719372 and 015.015.042) (J.S.), the Bill & Melinda Gates Foundation (OPP1156262 to R.W.S.), an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.) and an AMC PhD Scholarship (A.C.M.). L.R. was funded by the AMC as part of the local scientific research incentive policy. Funding Information: We thank Tim Beaumont and Sabrina Merat (AIMM) for providing sequences and data on AT1209. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. KewaliRaman. We thank Rashmi Ravichandran and Neil P King for providing the I53-50B.4PT1 protein. This research was supported by the Fondation Dormeur, Vaduz (to R.W.S. and M.J.v.G.), an AMC Fellowship from Amsterdam UMC (M.J.v.G.), a Vici grant from the Netherlands Organization for Scientific Research (NWO) (R.W.S.), a Vidi and Aspasia grant from the NWO (grant numbers 91719372 and 015.015.042) (J.S.), the Bill & Melinda Gates Foundation (OPP1156262 to R.W.S.), an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.) and an AMC PhD Scholarship (A.C.M.). L.R. was funded by the AMC as part of the local scientific research incentive policy. Funding Information: Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. For predicting the structures of (mutant versions of) gl_AR3C and gl-HEPC74 Fabs AlphaFold-2.2.0 Multimer was used. Code available at: https://github.com/deepmind/alphafold . , – Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
day = "1",
doi = "https://doi.org/10.1038/s41467-023-39690-0",
language = "English",
volume = "14",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}