1. Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1.
- Author
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Griffith S, Muir L, Suchanek O, Hope J, Pade C, Gibbons JM, Tuong ZK, Fung A, Touizer E, Rees-Spear C, Nans A, Roustan C, Alguel Y, Fink D, Orkin C, Deayton J, Anderson J, Gupta RK, Doores KJ, Cherepanov P, McKnight Á, Clatworthy M, and McCoy LE
- Abstract
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.- Published
- 2024
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