title: Immunosilencing a highly immunogenic protein trimerization domain.
abstract: Many therapeutic proteins and protein subunit vaccines contain heterologous trimerization domains, such as the widely used GCN4-based isoleucine zipper (IZ) and the T4 bacteriophage fibritin foldon (Fd) trimerization domains. We found that these domains induced potent anti-IZ or anti-Fd antibody responses in animals when fused to an HIV-1 envelope glycoprotein (Env) immunogen. To dampen IZ-induced responses, we constructed an IZ domain containing four N-linked glycans (IZN4) to shield the underlying protein surface. When fused to two different vaccine antigens, HIV-1 Env and influenza hemagglutinin (HA), IZN4 strongly reduced the antibody responses against the IZ, but did not affect the antibody titers against Env or HA. Silencing of immunogenic multimerization domains with glycans might be relevant for therapeutic proteins and protein vaccines.
authors: From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and.
authors: Kwinten
authors: K
authors: Sliepen
authors: From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and.
authors: Thijs
authors: T
authors: van Montfort
authors: From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and.
authors: Mark
authors: M
authors: Melchers
authors: From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and.
authors: Gözde
authors: G
authors: Isik
authors: From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and Weill Medical College of Cornell University, New York, New York 10065 rws2002@med.cornell.edu.
authors: Rogier W
authors: RW
authors: Sanders
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D058105:Polymerization; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
chemical_list: D011506:Proteins
keywords: human immunodeficiency virus (HIV); humoral response; influenza; protein engineering; vaccine
references: J Virol. 2007 Jun;81(11):5579-93
references: 17360741
references: Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8577-82
references: 24843166
references: J Virol. 2008 Jul;82(13):6200-8
references: 18417563
references: Lancet Neurol. 2005 Jul;4(7):403-12
references: 15963443
references: J Virol. 2010 Apr;84(7):3270-9
references: 20053749
references: J Immunol. 2014 May 15;192(10):4628-35
references: 24729614
references: Vaccine. 2008 Nov 18;26(49):6189-99
references: 18852005
references: PLoS One. 2010;5(9). pii: e12466. doi: 10.1371/journal.pone.0012466
references: 20824188
references: J Virol. 2005 Oct;79(19):12148-63
references: 16160142
references: Ann Rheum Dis. 2007 Feb;66(2):253-6
references: 16793840
references: Nature. 1994 Sep 1;371(6492):80-3
references: 8072533
references: Science. 1993 Nov 26;262(5138):1401-7
references: 8248779
references: Mol Cancer Ther. 2009 Jun;8(6):1515-25
references: 19509255
references: J Biol Chem. 2012 Jul 13;287(29):24239-54
references: 22645128
references: Self Nonself. 2010 Oct;1(4):314-322
references: 21487506
references: J Virol. 2002 Mar;76(6):2606-16
references: 11861826
references: J Immunol. 2013 Jul 1;191(1):44-51
references: 23740950
references: J Virol. 2001 Feb;75(3):1165-71
references: 11152489
references: Structure. 1997 Jun 15;5(6):789-98
references: 9261070
references: J Biol Chem. 1999 Jan 1;274(1):418-23
references: 9867859
references: J Virol. 2010 Oct;84(19):10366-74
references: 20686020
references: Annu Rev Immunol. 2006;24:739-69
references: 16551265
references: J Biol Chem. 1990 Sep 15;265(26):15599-605
references: 2144287
references: Nat Protoc. 2010 Apr;5(4):725-38
references: 20360767
references: PLoS One. 2010;5(5):e10645
references: 20498717
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W214-9
references: 15980456
references: Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18542-7
references: 25512514
references: PLoS Pathog. 2008;4(10):e1000171
references: 18833294
references: PLoS One. 2013;8(8):e71072
references: 23951084
references: Virology. 2009 Dec 5;395(1):33-44
references: 19815247
references: J Immunol. 1997 Jul 1;159(1):279-89
references: 9200464
references: Mol Ther. 2001 Mar;3(3):368-74
references: 11273779
references: J Biol Chem. 1995 Jun 16;270(24):14756-61
references: 7782341
references: J Virol. 2014 Jan;88(1):699-704
references: 24155380
references: Blood. 2011 Oct 6;118(14):3811-7
references: 21841160
references: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11311-6
references: 18678888
references: Mol Immunol. 2007 May;44(12):3112-21
references: 17374396
references: J Biol Chem. 2011 Jun 24;286(25):22250-61
references: 21515681
references: J Virol. 2002 Sep;76(17):8875-89
references: 12163607
references: J Virol. 2002 May;76(9):4634-42
references: 11932429
references: Retrovirology. 2011;8:48
references: 21689404
references: Immunol Rev. 2010 Jul;236:265-75
references: 20636822
references: J Clin Oncol. 2001 Jul 1;19(13):3280-7
references: 11432896
references: PLoS One. 2011;6(1):e16555
references: 21304591
references: J Virol. 2013 Dec;87(24):13239-51
references: 24067980
references: J Virol. 2012 Mar;86(5):2488-500
references: 22205734
references: J Exp Med. 2010 Aug 30;207(9):2003-17
references: 20679401
references: Vaccine. 2011 Feb 11;29(8):1545-50
references: 21219983
references: Science. 2013 Nov 1;342(6158):592-8
references: 24179220
references: J Mol Biol. 2004 Apr 2;337(4):905-15
references: 15033360
references: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12111-6
references: 22773820