Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2018-09-18
Date Acceptance
2018-08-17
Citation
Cell Reports, 2018, 24 (12), pp.3324-3338.e5
ISSN
2211-1247
Publisher
Elsevier
Start Page
3324
End Page
3338.e5
Journal / Book Title
Cell Reports
Volume
24
Issue
12
Copyright Statement
© 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor
Commission of the European Communities
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000444924100021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
681137
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
IMMUNODEFICIENCY-VIRUS TYPE-1
N-LINKED GLYCANS
CRYO-EM STRUCTURE
NEUTRALIZING ANTIBODIES
STRUCTURAL BASIS
VACCINE DESIGN
NEGATIVE-IONS
GP41-GP120 INTERFACE
GLYCOPROTEIN COMPLEX
NONHUMAN-PRIMATES
Publication Status
Published
Date Publish Online
2018-09-18