Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers
Yoann Aldon,
Paul F. McKay,
Joel Allen,
Gabriel Ozorowski,
Réka Felfödiné Lévai,
Monica Tolazzi,
Paul Rogers,
Linling He,
Natalia de Val,
Katalin Fábián,
Gabriella Scarlatti,
Jiang Zhu,
Andrew B. Ward,
Max Crispin,
Robin J. Shattock
Affiliations
Yoann Aldon
Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK
Paul F. McKay
Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK
Joel Allen
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK
Gabriel Ozorowski
Department of Integrative Structural and Computational Biology, Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA
Réka Felfödiné Lévai
Department of Immunology, National Food Chain Safety Office, Directorate of Veterinary Medicinal Products, Budapest, Hungary
Monica Tolazzi
Viral Evolution and Transmission Unit, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
Paul Rogers
Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK
Linling He
Department of Integrative Structural and Computational Biology, Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA
Natalia de Val
Department of Integrative Structural and Computational Biology, Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA
Katalin Fábián
Department of Immunology, National Food Chain Safety Office, Directorate of Veterinary Medicinal Products, Budapest, Hungary
Gabriella Scarlatti
Viral Evolution and Transmission Unit, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
Jiang Zhu
Department of Integrative Structural and Computational Biology, Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA
Andrew B. Ward
Department of Integrative Structural and Computational Biology, Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA
Max Crispin
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
Robin J. Shattock
Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK; Corresponding author
Summary: 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. Keywords: HIV-1, Env, trimer, bNAb, DNA, cell-based ELISA, muscle cells, cytoplasmic tail, transmembrane
