Distinct allosteric remodeling of HIV-1 Env dynamics on virions by gp41-directed antibodies reveals two modes of neutralization

Xu, W.; Gonepudi, N. K.; Liu, J.; He, Y.; Katte, R.; Wang, R.; Awuah, H. B.; Han, Y.; Yu, J.; Zhang, B.; Hu, B.; Ho, D. D.; Acharya, P.; Kwong, P. D.; Lu, M.

doi:10.64898/2026.01.27.702099

bioRxiv · 10.64898/2026.01.27.702099

Distinct allosteric remodeling of HIV-1 Env dynamics on virions by gp41-directed antibodies reveals two modes of neutralization

Xu, W.·Gonepudi, N. K.·Liu, J.·He, Y.·Katte, R.·Wang, R.·Awuah, H. B.·Han, Y.·Yu, J.·Zhang, B.·Hu, B.·Ho, D. D.·Acharya, P.·Kwong, P. D.·Lu, M.

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Abstract

HIV-1 envelope glycoprotein (Env), a gp120-gp41 trimer, undergoes coordinated conformational changes that drive membrane fusion and allow immune evasion by transiently concealing neutralization-sensitive epitopes. Most broadly neutralizing antibodies (bNAbs) target gp120, whereas a distinct subset recognizes conserved gp41 regions, such as the fusion peptide and the membrane-proximal external region; however, their impact on Env dynamics and associated neutralization mechanisms remains unclear. Using bioorthogonal tagging for single-molecule FRET, we monitored real-time bNAb-induced conformational sampling of Env on intact virions. Most gp41-directed bNAbs allosterically stabilized the prefusion-closed (PC) state, whereas the bivalent 10E8.4/iMab favored both PC and CD4-bound open (predominant) states. Antibodies redistributed the conformational populations of Env with modest kinetic effects, preserving the sequential transition pathway. These findings reveal two modes of neutralization for gp41-directed antibodies: fixing the prefusion-closed conformation and opening it, in both cases via long-range allosteric control of Env dynamics.

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Xu, W., Gonepudi, N. K., Liu, J., He, Y., Katte, R., Wang, R., Awuah, H. B., Han, Y., Yu, J., Zhang, B., Hu, B., Ho, D. D., Acharya, P., Kwong, P. D., Lu, M.. 2026-01-28. Distinct allosteric remodeling of HIV-1 Env dynamics on virions by gp41-directed antibodies reveals two modes of neutralization. https://doi.org/10.64898/2026.01.27.702099

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