Super Potent Bispecific Llama VHH Antibodies Neutralize HIV via a Combination of gp41 and gp120 Epitopes.
Aids
HIV
Llama Antibodies
bi-specific VHH
co-crystallisation
competition studies
epitope mapping
pepscan
Journal
Antibodies (Basel, Switzerland)
ISSN: 2073-4468
Titre abrégé: Antibodies (Basel)
Pays: Switzerland
ID NLM: 101587489
Informations de publication
Date de publication:
18 Jun 2019
18 Jun 2019
Historique:
received:
17
03
2019
revised:
19
05
2019
accepted:
30
05
2019
entrez:
24
9
2019
pubmed:
24
9
2019
medline:
24
9
2019
Statut:
epublish
Résumé
Broad and potent neutralizing llama single domain antibodies (VHH) against HIV-1 targeting the CD4 binding site (CD4bs) have previously been isolated upon llama immunization. Here we describe the epitopes of three additional VHH groups selected from phage libraries. The 2E7 group binds to a new linear epitope in the first heptad repeat of gp41 that is only exposed in the fusion-intermediate conformation. The 1B5 group competes with co-receptor binding and the 1F10 group interacts with the crown of the gp120 V3 loop, occluded in native Env. We present biophysical and structural details on the 2E7 interaction with gp41. In order to further increase breadth and potency, we constructed bi-specific VHH. The combination of CD4bs VHH (J3/3E3) with 2E7 group VHH enhanced strain-specific neutralization with potencies up to 1400-fold higher than the mixture of the individual VHHs. Thus, these new bivalent VHH are potent new tools to develop therapeutic approaches or microbicide intervention.
Identifiants
pubmed: 31544844
pii: antib8020038
doi: 10.3390/antib8020038
pmc: PMC6640723
pii:
doi:
Types de publication
Journal Article
Langues
eng
Références
Nat Struct Biol. 1999 May;6(5):458-63
pubmed: 10331874
J Virol. 2000 Sep;74(18):8358-67
pubmed: 10954535
Antimicrob Agents Chemother. 2002 Jun;46(6):1896-905
pubmed: 12019106
J Virol. 2003 Mar;77(5):2859-65
pubmed: 12584309
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
pubmed: 15299926
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
J Virol. 2005 Aug;79(16):10108-25
pubmed: 16051804
J Immunol. 2005 Oct 1;175(7):4265-73
pubmed: 16177066
Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82
pubmed: 16369096
Nat Struct Mol Biol. 2006 Aug;13(8):740-7
pubmed: 16862157
Biotechnol Bioeng. 2007 Feb 15;96(3):483-94
pubmed: 16948170
J Virol. 2006 Dec;80(23):11776-90
pubmed: 16971434
J Virol. 1991 Sep;65(9):4832-8
pubmed: 1714520
Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):32-41
pubmed: 17164524
Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10134-7
pubmed: 1719545
FEBS Lett. 2007 May 22;581(11):2150-5
pubmed: 17320081
J Virol. 2008 Dec;82(24):12069-81
pubmed: 18842738
Nature. 2009 Apr 2;458(7238):636-40
pubmed: 19287373
Science. 2009 Oct 9;326(5950):285-9
pubmed: 19729618
PLoS One. 2010 Jan 20;5(1):e8805
pubmed: 20098712
PLoS One. 2010 May 05;5(5):e10482
pubmed: 20463957
Science. 2010 Aug 13;329(5993):856-61
pubmed: 20616233
Science. 2010 Sep 3;329(5996):1168-74
pubmed: 20643915
Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20565-70
pubmed: 21059953
PLoS Pathog. 2010 Nov 11;6(11):e1001182
pubmed: 21085615
PLoS Pathog. 2010 Nov 18;6(11):e1001195
pubmed: 21124990
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):271-81
pubmed: 21460445
PLoS One. 2011 Apr 01;6(4):e17665
pubmed: 21483777
J Transl Med. 2011 Apr 12;9:40
pubmed: 21486446
Science. 2011 Sep 16;333(6049):1633-7
pubmed: 21764753
Nature. 2011 Sep 22;477(7365):466-70
pubmed: 21849977
AIDS Res Hum Retroviruses. 2012 Feb;28(2):198-205
pubmed: 21864083
Acta Crystallogr D Biol Crystallogr. 2011 Oct;67(Pt 10):902-6
pubmed: 21931222
Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):875-80
pubmed: 22219363
J Virol. 2012 Mar;86(6):3393-7
pubmed: 22258252
PLoS One. 2012;7(3):e33298
pubmed: 22438910
J Exp Med. 2012 Jun 4;209(6):1091-103
pubmed: 22641382
PLoS Comput Biol. 2012;8(6):e1002527
pubmed: 22685388
J Exp Med. 2012 Jul 30;209(8):1469-79
pubmed: 22826297
Nature. 2012 Dec 6;492(7427):118-22
pubmed: 23103874
Nature. 2012 Nov 15;491(7424):406-12
pubmed: 23151583
J Virol. 2013 Jan;87(2):1137-49
pubmed: 23152508
Nat Immunol. 2013 Jan;14(1):1-5
pubmed: 23238748
Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):513-8
pubmed: 23267106
PLoS Pathog. 2013 Mar;9(3):e1003202
pubmed: 23505368
Science. 2013 Dec 20;342(6165):1477-83
pubmed: 24179159
Science. 2013 Dec 20;342(6165):1484-90
pubmed: 24179160
J Biol Chem. 2014 Oct 24;289(43):29912-26
pubmed: 25160627
Nature. 2014 Oct 23;514(7523):455-61
pubmed: 25296255
PLoS Pathog. 2014 Dec 18;10(12):e1004552
pubmed: 25522326
Vaccine. 2015 Apr 21;33(17):2086-95
pubmed: 25769884
Nature. 2015 Jun 25;522(7557):487-91
pubmed: 25855300
J Virol. 2015 Jul;89(13):6685-94
pubmed: 25878112
J Virol. 2015 Dec;89(24):12501-12
pubmed: 26446600
Cell. 2016 Jun 16;165(7):1609-1620
pubmed: 27315478
Cell. 2016 Jun 16;165(7):1621-1631
pubmed: 27315479
J Virol. 1993 Jul;67(7):3978-88
pubmed: 7685405
Nature. 1997 May 22;387(6631):426-30
pubmed: 9163431