Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1.

Autor:	Griffith S; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Muir L; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Suchanek O; Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK.; Cambridge University Hospitals NHS Foundation Trust, and NIHR Cambridge Biomedical Research Centre, Cambridge, UK., Hope J; Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute, London, UK., Pade C; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK., Gibbons JM; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK., Tuong ZK; Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK.; Cellular Genetics, Wellcome Sanger Institute, Cambridge, UK.; Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia., Fung A; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Touizer E; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Rees-Spear C; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Nans A; Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK., Roustan C; Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK., Alguel Y; Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute, London, UK., Fink D; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK., Orkin C; SHARE collaborative, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK., Deayton J; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK., Anderson J; Homerton University Hospital NHS Foundation, London, UK., Gupta RK; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Doores KJ; Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK., Cherepanov P; Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute, London, UK.; Department of Infectious Disease, St-Mary's Campus, Imperial College London, London, UK., McKnight Á; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK., Clatworthy M; Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK.; Cambridge University Hospitals NHS Foundation Trust, and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.; Cellular Genetics, Wellcome Sanger Institute, Cambridge, UK.; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK., McCoy LE; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 06. Date of Electronic Publication: 2024 Feb 06.
DOI:	10.1101/2024.02.05.578789
Abstrakt:	Immunological determinants favouring emergence of broadly neutralising antibodies are crucial to the development of HIV-1 vaccination strategies. Here, we combined RNAseq and B cell cloning approaches to isolate a broadly neutralising antibody (bnAb) ELC07 from an individual living with untreated HIV-1. Using single particle cryogenic electron microscopy (cryo-EM), we show that the antibody recognises a conformational epitope at the gp120-gp41 interface. ELC07 binds the closed state of the viral glycoprotein causing considerable perturbations to the gp41 trimer core structure. Phenotypic analysis of memory B cell subsets from the ELC07 bnAb donor revealed a lack of expected HIV-1-associated dysfunction, specifically no increase in CD21 - /CD27 - cells was observed whilst the resting memory (CD21 + /CD27 + ) population appeared preserved despite uncontrolled HIV-1 viraemia. Moreover, single cell transcriptomes of memory B cells from this bnAb donor showed a resting memory phenotype irrespective of the epitope they targeted or their ability to neutralise diverse strains of HIV-1. Strikingly, single memory B cells from the ELC07 bnAb donor were transcriptionally similar to memory B cells from HIV-negative individuals. Our results demonstrate that potent bnAbs can arise without the HIV-1-induced dysregulation of the memory B cell compartment and suggest that sufficient levels of antigenic stimulation with a strategically designed immunogen could be effective in HIV-negative vaccine recipients. Competing Interests: R.K.G. has received honoraria for consulting and educational activities from Gilead, GSK, Janssen, and Moderna.
Databáze:	MEDLINE
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