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Nat Commun. 2017 Nov 21;8(1):1655. doi: 10.1038/s41467-017-01549-6.

Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding.

Kulp DW1,2,3,4, Steichen JM1,2,3, Pauthner M1,2,3, Hu X1,2,3, Schiffner T1,2,3, Liguori A1,2,3, Cottrell CA2,3,5, Havenar-Daughton C3,6, Ozorowski G2,3,5, Georgeson E1,2,3, Kalyuzhniy O1,2,3, Willis JR1,2,3, Kubitz M1,2,3, Adachi Y1,2,3, Reiss SM3,6, Shin M2,3,5, de Val N2,3,5, Ward AB2,3,5, Crotty S3,6,7, Burton DR1,2,3,8, Schief WR9,10,11,12.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
2
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
3
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA.
4
Vaccine and Immune Therapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA.
5
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
6
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
7
Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA.
8
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA.
9
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
10
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
11
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
12
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA. schief@scripps.edu.

Abstract

Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity. In rabbit immunizations with native-like trimers of the 327c isolate, improved trimers suppress elicitation of V3-directed and tier-1 neutralizing antibodies and induce robust autologous tier-2 neutralization, unlike a first-generation trimer. The improved native-like trimers from diverse HIV isolates, and the design methods, have promise to assist in the development of a HIV vaccine.

PMID:
29162799
PMCID:
PMC5698488
DOI:
10.1038/s41467-017-01549-6
[Indexed for MEDLINE]
Free PMC Article

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