Proteins mimicking epitope of HIV-1 virus neutralizing antibody induce virus-neutralizing sera in mice.
AIDS Vaccines
/ immunology
Amino Acid Sequence
Animals
Antibodies, Neutralizing
/ blood
Antigens, Viral
/ chemistry
Disease Models, Animal
Epitopes
/ chemistry
HIV Antibodies
/ blood
HIV Envelope Protein gp120
/ immunology
HIV Infections
/ immunology
HIV-1
/ immunology
Humans
Immunoglobulin G
/ blood
Mice
Models, Molecular
Protein Conformation
Albumin-binding domain scaffold
Antibody paratope mimetics
Combinatorial protein library
HIV-1 vaccine
Neutralizing antibody
Protein docking
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
17
04
2019
revised:
28
06
2019
accepted:
04
07
2019
entrez:
24
9
2019
pubmed:
24
9
2019
medline:
12
2
2020
Statut:
ppublish
Résumé
The development of an effective vaccine preventing HIV-1 infection is hindered by the enormous antigenic variability and unique biochemical and immunological properties of HIV-1 Env glycoprotein, the most promising target for HIV-1 neutralizing antibody. Functional studies of rare elite neutralizers led to the discovery of broadly neutralizing antibodies. We employed a highly complex combinatorial protein library derived from a 5 kDa albumin-binding domain scaffold, fused with support protein of total 38 kDa, to screen for binders of broadly neutralizing antibody VRC01 paratope. The most specific binders were used for immunization of experimental mice to elicit Env-specific antibodies and to test their neutralization activity using a panel of HIV-1 clade C and B pseudoviruses. Three most specific binders designated as VRA017, VRA019, and VRA177 exhibited high specificity to VRC01 antibody. Immunized mice produced Env-binding antibodies which neutralize eight of twelve HIV-1 Tier 2 pseudoviruses. Molecular modelling revealed a shape complementarity between VRA proteins and a part of VRC01 gp120 interacting surface. This strategy based on the identification of protein replicas of broadly neutralizing antibody paratope represents a novel approach in HIV-1 vaccine development. This approach is not affected by low immunogenicity of neutralization-sensitive epitopes, variability, and unique biochemical properties of HIV-1 Env used as a crucial antigen in the majority of contemporary tested vaccines. FUND: Czech Health Research Council 15-32198A, Ministry of Health, Czech Republic.
Sections du résumé
BACKGROUND
BACKGROUND
The development of an effective vaccine preventing HIV-1 infection is hindered by the enormous antigenic variability and unique biochemical and immunological properties of HIV-1 Env glycoprotein, the most promising target for HIV-1 neutralizing antibody. Functional studies of rare elite neutralizers led to the discovery of broadly neutralizing antibodies.
METHODS
METHODS
We employed a highly complex combinatorial protein library derived from a 5 kDa albumin-binding domain scaffold, fused with support protein of total 38 kDa, to screen for binders of broadly neutralizing antibody VRC01 paratope. The most specific binders were used for immunization of experimental mice to elicit Env-specific antibodies and to test their neutralization activity using a panel of HIV-1 clade C and B pseudoviruses.
FINDINGS
RESULTS
Three most specific binders designated as VRA017, VRA019, and VRA177 exhibited high specificity to VRC01 antibody. Immunized mice produced Env-binding antibodies which neutralize eight of twelve HIV-1 Tier 2 pseudoviruses. Molecular modelling revealed a shape complementarity between VRA proteins and a part of VRC01 gp120 interacting surface.
INTERPRETATION
CONCLUSIONS
This strategy based on the identification of protein replicas of broadly neutralizing antibody paratope represents a novel approach in HIV-1 vaccine development. This approach is not affected by low immunogenicity of neutralization-sensitive epitopes, variability, and unique biochemical properties of HIV-1 Env used as a crucial antigen in the majority of contemporary tested vaccines. FUND: Czech Health Research Council 15-32198A, Ministry of Health, Czech Republic.
Identifiants
pubmed: 31544770
pii: S2352-3964(19)30450-5
doi: 10.1016/j.ebiom.2019.07.015
pmc: PMC6796546
pii:
doi:
Substances chimiques
AIDS Vaccines
0
Antibodies, Neutralizing
0
Antigens, Viral
0
Epitopes
0
HIV Antibodies
0
HIV Envelope Protein gp120
0
Immunoglobulin G
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
247-256Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
Références
Cell. 2016 Sep 8;166(6):1471-1484.e18
pubmed: 27610571
Science. 2016 Mar 25;351(6280):1458-63
pubmed: 27013733
Immunol Lett. 2015 Jul;166(1):36-44
pubmed: 26021827
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6049-54
pubmed: 23524883
Proteins. 2014 Jun;82(6):975-89
pubmed: 24549990
Retrovirology. 2018 Sep 12;15(1):63
pubmed: 30208933
Nat Commun. 2016 Jun 28;7:12040
pubmed: 27349805
AIDS Res Ther. 2014 Aug 01;11:23
pubmed: 25120578
Cell. 2015 Jun 18;161(7):1505-15
pubmed: 26091035
Mol Syst Biol. 2011 Oct 11;7:539
pubmed: 21988835
Clin Pharmacol Ther. 2018 Dec;104(6):1062-1073
pubmed: 30099743
Proteins. 2013 Dec;81(12):2159-66
pubmed: 23996272
Protein Cell. 2018 Jul;9(7):596-615
pubmed: 29667004
J Mol Biol. 1993 Dec 5;234(3):779-815
pubmed: 8254673
Anal Biochem. 2011 Jan 1;408(1):95-104
pubmed: 20732292
Retrovirology. 2018 Jul 28;15(1):53
pubmed: 30055635
Science. 2011 Nov 25;334(6059):1097-103
pubmed: 21998254
Protein Cell. 2015 Oct;6(10):774-9
pubmed: 26264490
J Virol. 2002 Sep;76(17):8875-89
pubmed: 12163607
Proteins. 2012 Mar;80(3):774-89
pubmed: 22113774
J Virol. 2015 May;89(10):5318-29
pubmed: 25740988
Sci Adv. 2018 Nov 21;4(11):eaau6769
pubmed: 30474059
Cell Rep. 2017 Aug 22;20(8):1805-1817
pubmed: 28834745
PLoS Biol. 2010 Jun 29;8(6):e1000412
pubmed: 20613859
Annu Rev Immunol. 2016 May 20;34:635-59
pubmed: 27168247
Front Immunol. 2018 Feb 28;9:345
pubmed: 29541072
Autoimmunity. 2017 Mar;50(2):102-113
pubmed: 28100093
J Virol. 2015 Oct;89(20):10383-98
pubmed: 26246566
Proteins. 2006 Nov 1;65(2):392-406
pubmed: 16933295
PLoS Pathog. 2013;9(5):e1003342
pubmed: 23658524
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10275-80
pubmed: 24982157
Retrovirology. 2018 Sep 5;15(1):61
pubmed: 30185183
N Engl J Med. 2009 Dec 3;361(23):2209-20
pubmed: 19843557
Science. 2011 Sep 16;333(6049):1633-7
pubmed: 21764753
PLoS One. 2016 Feb 05;11(2):e0148497
pubmed: 26848589
Int J Mol Sci. 2018 Oct 09;19(10):null
pubmed: 30304852
Vaccine. 2008 Mar 17;26(12):1541-51
pubmed: 18304708
Nature. 2013 Nov 14;503(7475):277-80
pubmed: 24172896
J Biol Chem. 2010 Jul 2;285(27):20860-9
pubmed: 20439465
J Transl Med. 2011 Jan 27;9 Suppl 1:S2
pubmed: 21284901
Immunity. 2016 Sep 20;45(3):483-496
pubmed: 27617678
J Mol Biol. 2003 Jan 10;325(2):325-35
pubmed: 12488098
Curr HIV Res. 2018;16(1):21-28
pubmed: 29173180
Proteins. 1993 May;16(1):1-7
pubmed: 8497480
J Exp Med. 2013 Apr 8;210(4):655-63
pubmed: 23530120
Science. 2015 Jul 10;349(6244):156-61
pubmed: 26089355
J Biol Chem. 2002 Mar 8;277(10):8114-20
pubmed: 11751858
Science. 2010 Aug 13;329(5993):811-7
pubmed: 20616231
J Virol. 2018 Dec 10;93(1):
pubmed: 30305355
Curr Opin Immunol. 2018 Aug;53:143-151
pubmed: 29775847
Nat Commun. 2016 Feb 24;7:10618
pubmed: 26907590
Cell. 2014 Feb 13;156(4):633-48
pubmed: 24529371
J Exp Med. 2017 Aug 7;214(8):2283-2302
pubmed: 28698284
Cell Rep. 2015 Apr 28;11(4):539-50
pubmed: 25892233
Nat Immunol. 2018 Nov;19(11):1179-1188
pubmed: 30333615
Science. 2010 Aug 13;329(5993):856-61
pubmed: 20616233
Curr Protoc Immunol. 2005 Jan;Chapter 12:Unit 12.11
pubmed: 18432938