eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody.
CCR5
CD4
HIV-1
eCD4-Ig
viral entry
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
15 07 2019
15 07 2019
Historique:
received:
13
03
2019
accepted:
23
04
2019
pubmed:
10
5
2019
medline:
27
5
2020
entrez:
10
5
2019
Statut:
epublish
Résumé
The engineered antibody-like entry inhibitor eCD4-Ig neutralizes every human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus isolate it has been tested against. The exceptional breadth of eCD4-Ig derives from its ability to closely and simultaneously emulate the HIV-1 receptor CD4 and coreceptors, either CCR5 or CXCR4. Here we investigated whether viral escape from eCD4-Ig is more difficult than that from CD4-Ig or the CD4-binding site antibody NIH45-46. We observed that a viral swarm selected with high concentrations of eCD4-Ig was increasingly resistant to but did not fully escape from eCD4-Ig. In contrast, viruses selected under the same conditions with CD4-Ig or NIH45-46 fully escaped from those inhibitors. eCD4-Ig-resistant viruses acquired unique changes in the V2 apex, V3, V4, and CD4-binding regions of the HIV-1 envelope glycoprotein (Env). Most of the alterations did not directly affect neutralization by eCD4-Ig or neutralizing antibodies. However, alteration of Q428 to an arginine or lysine resulted in markedly greater resistance to eCD4-Ig and CD4-Ig, with correspondingly dramatic losses in infectivity and greater sensitivity to a V3 antibody and to serum from an infected individual. Compensatory mutations in the V3 loop (N301D) and in the V2 apex (K171E) partially restored viral fitness without affecting serum or eCD4-Ig sensitivity. Collectively, these data suggest that multiple mutations will be necessary to fully escape eCD4-Ig without loss of viral fitness.
Identifiants
pubmed: 31068428
pii: JVI.00443-19
doi: 10.1128/JVI.00443-19
pmc: PMC6600210
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
CD4 Antigens
0
HIV Antibodies
0
HIV Envelope Protein gp120
0
gp120 protein, Human immunodeficiency virus 1
0
gp120 protein, Human immunodeficiency virus 2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI129868
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI091476
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI126623
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Microbiology.
Références
Mol Syst Biol. 2011 Oct 11;7:539
pubmed: 21988835
Antimicrob Agents Chemother. 2002 Jun;46(6):1896-905
pubmed: 12019106
PLoS Pathog. 2015 Aug 06;11(8):e1005090
pubmed: 26248318
Sci Transl Med. 2015 Dec 23;7(319):319ra206
pubmed: 26702094
PLoS Pathog. 2017 Dec 18;13(12):e1006786
pubmed: 29253851
J Biol Chem. 1999 Oct 1;274(40):28745-50
pubmed: 10497246
Science. 2017 Oct 6;358(6359):85-90
pubmed: 28931639
Nature. 2012 Dec 6;492(7427):118-22
pubmed: 23103874
J Exp Med. 2014 Nov 17;211(12):2361-72
pubmed: 25385756
Retrovirology. 2013 Jan 31;10:9
pubmed: 23369442
Nature. 2011 Nov 30;481(7379):81-4
pubmed: 22139420
Nat Med. 2005 Jun;11(6):615-22
pubmed: 15880120
Curr Opin HIV AIDS. 2017 May;12(3):294-301
pubmed: 28422793
Nature. 2014 Nov 6;515(7525):138-42
pubmed: 25186731
J Virol. 1995 Nov;69(11):6705-11
pubmed: 7474080
J Virol. 2018 Aug 29;92(18):
pubmed: 29976677
Nature. 2015 Jun 25;522(7557):487-91
pubmed: 25855300
Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4351-6
pubmed: 23426631
Nature. 2016 Jul 28;535(7613):556-60
pubmed: 27338952
Nature. 2017 Mar 23;543(7646):559-563
pubmed: 28289286
J Virol. 1999 Mar;73(3):2343-9
pubmed: 9971817
J Virol. 2016 Aug 12;90(17):7822-32
pubmed: 27334589
Science. 2013 Dec 20;342(6165):1484-90
pubmed: 24179160
Cell. 2015 Jun 4;161(6):1280-92
pubmed: 26004070
Cell. 2016 Jun 16;165(7):1609-1620
pubmed: 27315478
Immunol Rev. 2017 Jan;275(1):145-160
pubmed: 28133802
J Virol. 1998 Apr;72(4):2855-64
pubmed: 9525605
J Virol. 2008 Dec;82(24):12585-8
pubmed: 18842727
J Virol. 2017 Aug 24;91(18):
pubmed: 28679752
Virology. 1995 Feb 1;206(2):935-44
pubmed: 7531918
Annu Rev Immunol. 2016 May 20;34:635-59
pubmed: 27168247
Cell. 2016 Apr 7;165(2):449-63
pubmed: 26949186
Nat Commun. 2018 Feb 28;9(1):877
pubmed: 29491415
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11483-8
pubmed: 20534513
Nat Struct Mol Biol. 2017 Apr;24(4):370-378
pubmed: 28218750
J Virol. 1999 Jul;73(7):5373-80
pubmed: 10364284
Virus Res. 2016 Jun 15;218:57-70
pubmed: 26494166
J Virol. 2015 Oct 14;90(1):76-91
pubmed: 26468542
Nature. 2011 Nov 23;480(7377):336-43
pubmed: 22113616
J Virol. 2001 Feb;75(4):1990-5
pubmed: 11160699
Immunity. 2016 Nov 15;45(5):1108-1121
pubmed: 27851912
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17624-9
pubmed: 25422458
J Virol. 2017 Aug 10;91(17):
pubmed: 28615206
Nature. 2013 Nov 14;503(7475):277-80
pubmed: 24172896
Science. 2013 Dec 20;342(6165):1477-83
pubmed: 24179159
Cell. 2014 Aug 28;158(5):989-999
pubmed: 25131989
Nature. 2003 Mar 20;422(6929):307-12
pubmed: 12646921
Nature. 2015 Mar 5;519(7541):87-91
pubmed: 25707797
J Acquir Immune Defic Syndr. 2014 Aug 15;66(5):473-83
pubmed: 24853313
Immunity. 2018 May 15;48(5):855-871
pubmed: 29768174
Nature. 1996 Jun 20;381(6584):661-6
pubmed: 8649511
Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):13151-6
pubmed: 25157148
Science. 1999 Apr 30;284(5415):816-9
pubmed: 10221916
J Virol. 2015 Apr;89(8):4201-13
pubmed: 25631091
J Virol. 2005 Aug;79(16):10108-25
pubmed: 16051804
PLoS Pathog. 2018 Aug 20;14(8):e1007238
pubmed: 30125330
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7552-7
pubmed: 18490657
Cell. 2003 Jul 25;114(2):161-70
pubmed: 12887918
J Virol. 1992 Aug;66(8):5110-3
pubmed: 1321291
Science. 2007 Sep 28;317(5846):1930-4
pubmed: 17901336
Immunity. 2017 Apr 18;46(4):690-702
pubmed: 28423342
Science. 2010 Aug 13;329(5993):811-7
pubmed: 20616231
Immunol Rev. 2017 Jan;275(1):21-32
pubmed: 28133813
Nature. 2011 Sep 22;477(7365):466-70
pubmed: 21849977
J Virol. 2009 Aug;83(16):8289-92
pubmed: 19474095
Elife. 2017 May 26;6:
pubmed: 28548638
J Virol. 2000 Sep;74(18):8358-67
pubmed: 10954535
J Exp Med. 2013 Jun 3;210(6):1235-49
pubmed: 23712429
Sci Transl Med. 2019 Jul 24;11(502):
pubmed: 31341061
Nature. 2013 Apr 25;496(7446):469-76
pubmed: 23552890