HIV-1 vaccine design through minimizing envelope metastability

He, L.; Kumar, S.; Allen, J. J.; Huang, D.; Lin, X.; Mann, C. J.; Saye-Francisco, K. L.; Copps, J.; Sarkar, A.; Blizard, G. S.; Ozorowski, G.; Sok, D.; Crispin, M.; Ward, A. B.; Nemazee, D.; Burton, D. R.; Wilson, I. A.; Zhu, J.

doi:10.1101/361931

bioRxiv · 10.1101/361931

HIV-1 vaccine design through minimizing envelope metastability

He, L.·Kumar, S.·Allen, J. J.·Huang, D.·Lin, X.·Mann, C. J.·Saye-Francisco, K. L.·Copps, J.·Sarkar, A.·Blizard, G. S.·Ozorowski, G.·Sok, D.·Crispin, M.·Ward, A. B.·Nemazee, D.·Burton, D. R.·Wilson, I. A.·Zhu, J.

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Abstract

Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For ten strains across five clades, we demonstrate that gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTO with BG505 gp41ECTO of the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. Crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder (T/F) viruses and UFO trimers containing a consensus-based ancestral gp41ECTO suggest an evolutionary root of the metastability. Gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer. In mice and rabbits, gp140 nanoparticles induced more effective tier 2 neutralizing antibody response than trimers with statistical significance.\n\nHIGHLIGHTSO_LIgp41 is the main source of HIV-1 envelope metastability\nC_LIO_LIBG505 gp41 of the UFO design stabilizes gp140 trimers of diverse subtypes\nC_LIO_LIgp41 stabilization facilitates gp140 nanoparticle assembly and improves production\nC_LIO_LINanoparticles elicit tier 2 neutralizing antibodies more effectively than trimers\nC_LI

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He, L., Kumar, S., Allen, J. J., Huang, D., Lin, X., Mann, C. J., Saye-Francisco, K. L., Copps, J., Sarkar, A., Blizard, G. S., Ozorowski, G., Sok, D., Crispin, M., Ward, A. B., Nemazee, D., Burton, D. R., Wilson, I. A., Zhu, J.. 2018-07-04. HIV-1 vaccine design through minimizing envelope metastability. https://doi.org/10.1101/361931

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