@article{262aa3f5bfaa4351a9918f4a3d46fd80,
title = "Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors",
abstract = "Elicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. Six of the mAbs recognize the conserved E2 antigenic site 412–423 (AS412) and cross-neutralize diverse HCV genotypes. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Intriguingly, the anti-HCV activity of one antibody lineage is associated with maturation of the light chain (LC), whereas the other lineage is dependent on heavy-chain (HC) maturation. Crystal structures of GL precursors of the LC-dependent lineage in complex with AS412 offer critical insights into the maturation process of bnAbs to HCV, providing a scientific foundation for utilizing the mouse model to study AS412-targeting vaccine candidates.",
author = "Fernando Aleman and Netanel Tzarum and Leopold Kong and Kenna Nagy and Jiang Zhu and Wilson, {Ian A.} and Mansun Law",
note = "Funding Information: We thank Erick Giang, Andrew Honda, Jessica Reinhard, and Shaun Castillo for technical assistance; Alex Tarr and Jonathan Ball for E1E2 expression plasmids; and Takaji Wakita and Jens Bukh for HCVcc. This work was supported by NIH Grants AI079031 (to M.L.), AI106005 and AI123365 (to M.L. and I.A.W.), and AI123861 (to M.L. and J.Z.). X-ray datasets were collected at the APS beamline 23ID-B (GM/CA CAT) and SSRL beamline 12-2. The use of the APS was supported by the US Department of Energy (DOE), Basic Energy Sciences, Office of Science, under Contract DE-AC02-06CH11357. The use of the SSRL Structural Molecular Biology Program was supported by DOE Office of Biological and Environmental Research and by the NIH National Institute of General Medical Sciences (including P41GM103393) and the National Center for Research Resources (P41RR001209). This is manuscript 29637 from The Scripps Research Institute. Funding Information: ACKNOWLEDGMENTS. We thank Erick Giang, Andrew Honda, Jessica Reinhard, and Shaun Castillo for technical assistance; Alex Tarr and Jonathan Ball for E1E2 expression plasmids; and Takaji Wakita and Jens Bukh for HCVcc. This work was supported by NIH Grants AI079031 (to M.L.), AI106005 and AI123365 (to M.L. and I.A.W.), and AI123861 (to M.L. and J.Z.). X-ray datasets were collected at the APS beamline 23ID-B (GM/CA CAT) and SSRL beamline 12-2. The use of the APS was supported by the US Department of Energy (DOE), Basic Energy Sciences, Office of Science, under Contract DE-AC02-06CH11357. The use of the SSRL Structural Molecular Biology Program was supported by DOE Office of Biological and Environmental Research and by the NIH National Institute of General Medical Sciences (including P41GM103393) and the National Center for Research Resources (P41RR001209). This is manuscript 29637 from The Scripps Research Institute. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",
year = "2018",
month = jul,
day = "17",
doi = "https://doi.org/10.1073/pnas.1802378115",
language = "English",
volume = "115",
pages = "7569--7574",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "29",
}
