The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

Richard, J.; Grunst, M. W.; Niu, L.; Diaz-Salinas, M. A.; Tolbert, W. D.; Marchitto, L.; Zhou, F.; Bourassa, C.; Yang, D.; Chiu, T.-J.; Chen, H.-C.; Benlarbi, M.; Beaudoin-Bussieres, G.; Gottumukkala, S.; Li, W.; Dionne, K.; Belanger, E.; Chatterjee, D.; Medjahed, H.; Hendrickson, W. A.; Sodroski, J.; Lang, Z. C.; Morton, A. J.; Huang, R. K.; Matthies, D.; Smith, A. B.; Mothes, W.; Munro, J.; Pazgier, M.; Finzi, A.

doi:10.1101/2024.08.27.609961

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bioRxiv · 10.1101/2024.08.27.609961

The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

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Abstract

HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. Structural and conformational analyses reveal that CJF-III-288, in combination with anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation, This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.

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Richard, J., Grunst, M. W., Niu, L., Diaz-Salinas, M. A., Tolbert, W. D., Marchitto, L., Zhou, F., Bourassa, C., Yang, D., Chiu, T.-J., Chen, H.-C., Benlarbi, M., Beaudoin-Bussieres, G., Gottumukkala, S., Li, W., Dionne, K., Belanger, E., Chatterjee, D., Medjahed, H., Hendrickson, W. A., Sodroski, J., Lang, Z. C., Morton, A. J., Huang, R. K., Matthies, D., Smith, A. B., Mothes, W., Munro, J., Pazgier, M., Finzi, A.. 2024-08-27. The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC. https://doi.org/10.1101/2024.08.27.609961

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