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Cell. 2015 Dec 17;163(7):1702-15. doi: 10.1016/j.cell.2015.11.056.

Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes.

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
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
5
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
6
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
7
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, Center for HIV-1/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA.
8
International AIDS Vaccine Initiative, New York, NY 10004, USA.
9
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
10
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
11
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.
12
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: r.w.sanders@amc.uva.nl.

Abstract

The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs.

PMID:
26687358
PMCID:
PMC4732737
DOI:
10.1016/j.cell.2015.11.056
[Indexed for MEDLINE]
Free PMC Article
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