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

Griffith, S.; Muir, L.; Suchanek, O.; Hope, J.; Pade, C.; Gibbons, J. M.; Tuong, Z. K.; Fung, A.; Touizer, E.; Rees-Spear, C.; Nans, A.; Roustan, C.; Alguel, Y.; Fink, D.; Orkin, C.; Deayton, J.; Anderson, J.; Gupta, R. K.; Doores, K. J.; Cherepanov, P.; McKnight, A.; Clatworthy, M.; McCoy, L. E.

doi:10.1101/2024.02.05.578789

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bioRxiv · 10.1101/2024.02.05.578789

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

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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.

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Griffith, S., Muir, L., Suchanek, O., Hope, J., Pade, C., Gibbons, J. M., Tuong, Z. K., Fung, A., Touizer, E., Rees-Spear, C., Nans, A., Roustan, C., Alguel, Y., Fink, D., Orkin, C., Deayton, J., Anderson, J., Gupta, R. K., Doores, K. J., Cherepanov, P., McKnight, A., Clatworthy, M., McCoy, L. E.. 2024-02-06. Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1. https://doi.org/10.1101/2024.02.05.578789

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