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

Research output: Contribution to journalArticle

Abstract

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
Volume24
Issue number12
DOIs
Publication statusPublished - 2018

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HIV-1
Neutralizing Antibodies
Antibodies
DNA
Vaccines
Viral Vaccines
env Gene Products
Immunization
Glycosylation
Membranes
Muscle Cells
Nucleic Acids
Muscle
Epitopes
Vaccination
Coloring Agents
Stabilization
Display devices
Cells
RNA

Cite this

Aldon, Y., McKay, PF., Allen, J., Ozorowski, G., Felfödiné Lévai, R., Tolazzi, 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

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

In: Cell Reports, Vol. 24, No. 12, 2018, p. 3324-3338.

Research output: Contribution to journalArticle

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, vol. 24, no. 12, pp. 3324-3338. https://doi.org/10.1016/j.celrep.2018.08.051
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. / Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers. In: Cell Reports. 2018 ; Vol. 24, No. 12. pp. 3324-3338.
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