HIV Env trimers elicit NHP apex cross-neutralizing antibodies mimicking human bNAbs

Guenaga, J.; Guenaga, M.; Bale, S.; Phulera, S.; Zygouras, I.; Schleich, F.; Dopico, X. C.; Agrawal, S.; Ota, M.; Wilson, R.; Cluff, J.; Dzvelaia, T.; Mandolesi, M.; Walsh, A.; Melo, M.; Verkocky, L.; Irvine, D.; Corcoran, M.; Wilson, I. A.; Carnathan, D. G.; Silvestri, G.; Ward, A.; Ozorowski, G.; Karlsson Hedestam, G. B.; Wyatt, R. T.

doi:10.1101/2025.09.19.677470

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bioRxiv · 10.1101/2025.09.19.677470

HIV Env trimers elicit NHP apex cross-neutralizing antibodies mimicking human bNAbs

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Abstract

As a chronically replicating virus, HIV has evolved extreme sequence variability and effective shielding of functionally constrained spike protein determinants by host-derived glycans. Broadly neutralizing antibodies (bNAbs), though rare, can be isolated from people living with HIV, revealing conserved Env sites as key targets for vaccine development. One such target is the apex of the envelope glycoprotein (Env) spike. Here, we identified a vaccination strategy using heterologous HIV Env trimers covalently coupled to liposomes for multivalent display that resulted in the elicitation of cross-neutralizing HIV serum antibody responses in all immunized non-human primates (NHPs). Critically, we isolated a set of monoclonal antibodies (mAbs) that cross-neutralized multiple divergent HIV clinical isolates. High-resolution cryoEM structural analysis of mAbs from three different NHPs demonstrated that they targeted the Env trimer apex in a manner remarkably similar to that of the human infection-elicited, apex-directed bNAb PG9, representing a substantial advance in HIV vaccine development.

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Guenaga, J., Guenaga, M., Bale, S., Phulera, S., Zygouras, I., Schleich, F., Dopico, X. C., Agrawal, S., Ota, M., Wilson, R., Cluff, J., Dzvelaia, T., Mandolesi, M., Walsh, A., Melo, M., Verkocky, L., Irvine, D., Corcoran, M., Wilson, I. A., Carnathan, D. G., Silvestri, G., Ward, A., Ozorowski, G., Karlsson Hedestam, G. B., Wyatt, R. T.. 2025-09-21. HIV Env trimers elicit NHP apex cross-neutralizing antibodies mimicking human bNAbs. https://doi.org/10.1101/2025.09.19.677470

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