@article{6c05c41078f64996babd6027478c2ab4,
title = "Highly mutated antibodies capable of neutralizing N276 glycan-deficient HIV after a single immunization with an Env trimer",
abstract = "Elicitation of HIV broadly neutralizing antibodies (bnAbs) is challenging because unmutated bnAb precursors are rare and seldom bind HIV envelope glycoprotein (Env) trimers. One strategy to initiate bnAb responses is to use germline-targeting (GT) immunogens with high affinity to bnAb-class precursor B cells and then shepherd affinity maturation with booster immunogens that successively look more like native Env. In a mouse model where the frequency of VRC01-precursor (VRC01gHL) B cells mimics that of humans, we show that following a GT HIV Env trimer protein prime, VRC01-class B cells in the germinal center (GC) acquire high-affinity VRC01-class B cell somatic hypermutations (SHMs). Many GC-derived VRC01gHL antibodies robustly bind N276 glycan-deficient Env trimers and neutralize several N276 glycan-deficient tier 2 HIV strains. These results are encouraging for GT Env trimer vaccine designs and demonstrate accumulation of substantial SHMs, including deletions, uncommon point mutations, and functional bnAb features, after a single immunization.",
keywords = "broadly neutralizing antibody, envelope trimer, germline-targeting vaccine, human immunodeficiency virus",
author = "Lee, {Jeong Hyun} and Catherine Nakao and Michael Appel and Amber Le and Elise Landais and Oleksandr Kalyuzhniy and Xiaozhen Hu and Alessia Liguori and Mullen, {Tina Marie} and Bettina Groschel and Abbott, {Robert K.} and Devin Sok and Schief, {William R.} and Shane Crotty",
note = "Funding Information: We thank the La Jolla Institute for Immunology (LJI) sequencing core for NGS support, LJI Bioinformatics core for coding support, and LJI Flow cytometry core for sorting support. We also thank S. Menis for sharing updated codes for VRC01-class mutation analysis, K. Wiehe for sharing the Singularity container version of ARMADiLLO, and E. Ollmann-Saphire for providing lab equipment for antibody expression. This work was supported by the NIH CHAVD (UM1 AI144462 to S.C. W.R.S. and D.S.), NIH K99 AI145762 (R.K.A.), and the IAVI Neutralizing Antibody Center through the Collaboration for AIDS Vaccine Discovery grant OPP1196345/INV-008813, funded by the Bill and Melinda Gates Foundation (to W.R.S. and D.S.). The full list of IAVI's major donors is available at http://www.iavi.org. The FACSAria II Cell Sorter was acquired through the NIH Shared Instrumentation Grant (SIG) program (S10 RR027366). Conceptualization, J.H.L. and S.C.; methodology, J.H.L.; formal analysis, J.H.L. E.L. O.K. X.H. and A. Liguori; investigation, J.H.L. C.N. M.A. A. Le, O.K. X.H. and A. Liguori; resources, T.-M.M. B.G. B.A. and W.R.S.; data curation, J.H.L.; writing – original draft, J.H.L.; writing – review & editing, J.H.L. W.R.S. and S.C.; supervision and funding acquisition, D.S. W.R.S. and S.C. W.R.S. is an inventor on a patent application concerning the eOD-GT5 60-mer and MD39-GT3.1 Env trimer immunogens. Funding Information: We thank the La Jolla Institute for Immunology (LJI) sequencing core for NGS support, LJI Bioinformatics core for coding support, and LJI Flow cytometry core for sorting support. We also thank S. Menis for sharing updated codes for VRC01-class mutation analysis, K. Wiehe for sharing the Singularity container version of ARMADiLLO, and E. Ollmann-Saphire for providing lab equipment for antibody expression. This work was supported by the NIH CHAVD ( UM1 AI144462 to S.C., W.R.S., and D.S.), NIH K99 AI145762 (R.K.A.), and the IAVI Neutralizing Antibody Center through the Collaboration for AIDS Vaccine Discovery grant OPP1196345/INV-008813 , funded by the Bill and Melinda Gates Foundation (to W.R.S. and D.S.). The full list of IAVI{\textquoteright}s major donors is available at http://www.iavi.org . The FACSAria II Cell Sorter was acquired through the NIH Shared Instrumentation Grant (SIG) program ( S10 RR027366 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "8",
doi = "10.1016/j.celrep.2022.110485",
language = "English (US)",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}