National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
UM1AI144462
米国
Bill & Melinda Gates Foundation
INV-002916
米国
引用
ジャーナル: Nature / 年: 2022 タイトル: Long-primed germinal centres with enduring affinity maturation and clonal migration. 著者: Jeong Hyun Lee / Henry J Sutton / Christopher A Cottrell / Ivy Phung / Gabriel Ozorowski / Leigh M Sewall / Rebecca Nedellec / Catherine Nakao / Murillo Silva / Sara T Richey / Jonathan L ...著者: Jeong Hyun Lee / Henry J Sutton / Christopher A Cottrell / Ivy Phung / Gabriel Ozorowski / Leigh M Sewall / Rebecca Nedellec / Catherine Nakao / Murillo Silva / Sara T Richey / Jonathan L Torres / Wen-Hsin Lee / Erik Georgeson / Michael Kubitz / Sam Hodges / Tina-Marie Mullen / Yumiko Adachi / Kimberly M Cirelli / Amitinder Kaur / Carolina Allers / Marissa Fahlberg / Brooke F Grasperge / Jason P Dufour / Faith Schiro / Pyone P Aye / Oleksandr Kalyuzhniy / Alessia Liguori / Diane G Carnathan / Guido Silvestri / Xiaoying Shen / David C Montefiori / Ronald S Veazey / Andrew B Ward / Lars Hangartner / Dennis R Burton / Darrell J Irvine / William R Schief / Shane Crotty / 要旨: 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 ...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 (B) cells that last for at least 6 months. A 186-fold increase in B 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 B cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding B 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 cells. 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 B 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.