Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers

Y Aldon, PF McKay, J Allen, G Ozorowski, R Felfödiné Lévai, M Tolazzi, P Rogers, L He, N de Val, K Fábián, G Scarlatti, J Zhu, AB Ward, M Crispin, RJ Shattock

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The HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies. Aldon et al. developed membrane-bound and soluble stabilized HIV-1 Env trimer immunogens suitable for DNA/RNA or viral vector vaccines. The sequential iterative design and analysis in muscle cells have the potential to be used as a generalizable method for the expression of stabilized native-like trimers. © 2018 The Authors
Original languageEnglish
Pages (from-to)3324-3338
Number of pages15
JournalCell Reports
Issue number12
Publication statusPublished - 2018

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    Aldon, Y., McKay, PF., Allen, J., Ozorowski, G., Felfödiné Lévai, R., Tolazzi, M., Rogers, P., He, L., de Val, N., Fábián, K., Scarlatti, G., Zhu, J., Ward, AB., Crispin, M., & Shattock, RJ. (2018). Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers. Cell Reports, 24(12), 3324-3338. https://doi.org/10.1016/j.celrep.2018.08.051