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Cell Rep. 2017 Aug 22;20(8):1805-1817. doi: 10.1016/j.celrep.2017.07.077.

Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization.

Author information

1
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
2
Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
4
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
5
Department of Chemistry, University of Kansas, Lawrence, KS 66047, USA.
6
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
7
Microbial Systems Ecology, Department of Freshwater and Marine Ecology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam 1098 XH, the Netherlands.
8
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
9
Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
10
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA. Electronic address: rws2002@med.cornell.edu.

Abstract

The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).

PMID:
28834745
PMCID:
PMC5590011
DOI:
10.1016/j.celrep.2017.07.077
[Indexed for MEDLINE]
Free PMC Article

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