Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing

Steven W. de Taeye; Angela I. Schriek; Jeffrey C. Umotoy; Marloes Grobben; Judith A. Burger; Rogier W. Sanders; Gestur Vidarsson; Manfred Wuhrer; David Falck; Neeltje A. Kootstra; Marit J. van Gils

doi:10.1038/s42003-024-06659-8

Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing

Steven W. de Taeye^*, Angela I. Schriek, Jeffrey C. Umotoy, Marloes Grobben, Judith A. Burger, Rogier W. Sanders, Gestur Vidarsson, Manfred Wuhrer, David Falck, Neeltje A. Kootstra, Marit J. van Gils^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have the capacity to delay viral rebound when administered to people with HIV-1 (PWH) during anti-retroviral therapy (ART) interruption. To further enhance the performance of bNAbs through their Fc effector functions, in particular NK cell-mediated killing of HIV-1 infected cells, we have produced a panel of glyco-engineered (afucosylated) bNAbs with enhanced affinity for Fc gamma receptor IIIa. These afucosylated anti-HIV-1 bNAbs enhance NK cell activation and degranulation compared to fucosylated counterparts even at low antigen density. NK cells from PWH expressing exhaustion markers PD-1 and TIGIT are activated in a similar fashion by afucosylated bNAbs as NK cell from HIV-1 negative individuals. Killing of HIV-1 infected cells is most effective with afucosylated bNAbs 2G12, N6, PGT151 and PGDM1400, whereas afucosylated PGT121 and non-neutralizing antibody A32 only induce minor NK cell-mediated killing. These data indicate that the approach angle and affinity of Abs influence the capacity to induce antibody-dependent cellular cytotoxicity. Thus, afucosylated bNAbs have the capacity to induce NK cell-mediated killing of infected cells, which warrants further investigation of afucosylated bNAb administration in vivo, aiming for reduction of the viral reservoir and ART free durable control.

Original language	English
Article number	964
Number of pages	11
Journal	Communications Biology
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s42003-024-06659-8
Publication status	Published - 9 Aug 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We would like to thank the Amsterdam Cohort Studies (ACS) on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, and the Jan van Goyen Clinic, are part of The Netherlands HIV Monitoring Foundation. We would like to thank the NIH Aids reagent program for sharing materials and cell lines. We would like to thank Jan Nouta and Steinar Gijze for support with the liquid chromatography mass spectrometry measurements and data processing. Furthermore, we would like to thank Judith Burger for the generation of Env-pseudotyped viruses from the global panel. This work was supported by the Aidsfonds under grant number P-53301; amfAR Mathilde Krim fellowship under grant number 110425-73-RKRL; HealthHolland/Aidsfonds under grant number LSHM19101/P-44802; and HealthHolland/AMC under grant number 2019-1167. DAS:The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE81 partner repository with the dataset identifier PXD053363. All source data underlying the graphs in the figures and Supplementary figures is provided in the supplementary data 1 file. Any other data is available from the corresponding author upon request.

Funders	Funder number
Aidsfonds	P-53301
The amfAR Mathilde Krim fellowship	110425-73-RKRL
HealthHolland/Aidsfonds	LSHM19101/P-44802
HealthHolland/AMC	2019-1167

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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de Taeye, S. W., Schriek, A. I., Umotoy, J. C., Grobben, M., Burger, J. A., Sanders, R. W., Vidarsson, G., Wuhrer, M., Falck, D., Kootstra, N. A., & van Gils, M. J. (2024). Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing. Communications Biology, 7(1), Article 964. https://doi.org/10.1038/s42003-024-06659-8

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abstract = "Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have the capacity to delay viral rebound when administered to people with HIV-1 (PWH) during anti-retroviral therapy (ART) interruption. To further enhance the performance of bNAbs through their Fc effector functions, in particular NK cell-mediated killing of HIV-1 infected cells, we have produced a panel of glyco-engineered (afucosylated) bNAbs with enhanced affinity for Fc gamma receptor IIIa. These afucosylated anti-HIV-1 bNAbs enhance NK cell activation and degranulation compared to fucosylated counterparts even at low antigen density. NK cells from PWH expressing exhaustion markers PD-1 and TIGIT are activated in a similar fashion by afucosylated bNAbs as NK cell from HIV-1 negative individuals. Killing of HIV-1 infected cells is most effective with afucosylated bNAbs 2G12, N6, PGT151 and PGDM1400, whereas afucosylated PGT121 and non-neutralizing antibody A32 only induce minor NK cell-mediated killing. These data indicate that the approach angle and affinity of Abs influence the capacity to induce antibody-dependent cellular cytotoxicity. Thus, afucosylated bNAbs have the capacity to induce NK cell-mediated killing of infected cells, which warrants further investigation of afucosylated bNAb administration in vivo, aiming for reduction of the viral reservoir and ART free durable control.",

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Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing

Abstract

Bibliographical note

Funding

UN SDGs

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