Long-primed germinal centres with enduring affinity maturation and clonal migration

• Type of Material: Article
• Authors: Jeong Hyun Lee, La Jolla Institute for Immunology; Henry J Sutton, La Jolla Institute for Immunology; Christopher A Cottrell, Scripps Research Institute; Ivy Phung, La Jolla Institute for Immunology; Gabriel Ozorowski, Scripps Research Institute; Leigh M Sewall, Scripps Research Institute; Rebecca Nedellec, Scripps Research Institute; Catherine Nakao, La Jolla Inst Immunol; Murillo Silva, Scripps Research Institute; Sara T Richey, Scripps Research Institute; Jonathan L Torre, Scripps Research Institute; Wen-Hsin Lee, Scripps Research Institute; Erik Georgeson, Scripps Research Institute; Michael Kubitz, Scripps Research Institute; Sam Hodges, Scripps Research Institute; Tina-Marie Mullen, Scripps Research Institute; Yumiko Adachi, Scripps Research Institute; Kimberly M Cirelli, La Jolla Institute for Immunology; Amitinder Kaur, Tulane National Primate Research Center; Carolina Allers, Tulane National Primate Research Center; Marissa Fahlberg, Tulane National Primate Research Center; Brooke F Grasperge, Tulane National Primate Research Center; Jason P Dufour, Tulane National Primate Research Center; Faith Schiro, Tulane National Primate Research Center; Pyone P Aye, Tulane National Primate Research Center; Oleksandr Kalyuzhniy, Scripps Research Institute; Alessia Liguori, Scripps Research Institute; Diane G Carnathan, Scripps Research Institute; Guido Silvestri, Emory University; Xiaoying Shen, Duke University; David C Montefiori, Duke University; Ronald S Veazey, Tulane National Primate Research Center; Andrew B Ward, Scripps Research Institute; Lars Hangartner, Scripps Research Institute; Dennis R Burton, Scripps Research Institute; Darrell J Irvine, Scripps Research Institute; William R Schief, Scripps Research Institute; Shane Crotty, La Jolla Institute for Immunology
• Language: English
• Date: 2022-09-21
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Author(s), under exclusive licence to Springer Nature Limited 2022, corrected publication 2023Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-022-05216-9
• Title of Journal or Parent Work: NATURE
• Volume: 609
• Issue: 7929
• Start Page: 998
• End Page: +
• Grant/Funding Information: This work was supported in part by the National Institute of Allergy and Infectious Diseases of the NIH under award nos. CHAVI-ID UM1AI100663, CHAVD UM1AI144462, R01 AI125068, R01 AI136621 and P01AI048240; NIH NIAID SVEU contract no. HHSN272201300004I; and NIH NIAID NHP-CIL (contract nos. HHSN272201700022C and P51OD011104).; This work was also supported by the Bill and Melinda Gates Foundation (no. BMGF OPP1203211) and the Collaboration of AIDS Vaccine Discovery (no. OPP1115782/INV-002916).
• Keywords: Science & Technology - Other Topics; NEUTRALIZING ANTIBODY-RESPONSES; HIV; Science & Technology; CELLS; Multidisciplinary Sciences; DYNAMICS; NONHUMAN-PRIMATES
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery; Biology, Microbiology

Abstract

Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (BGC) cells that last for at least 6 months. A 186-fold increase in BGC cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells1,2. Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.