title: Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses.
abstract: A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs). Using a knock-in (KI) model of 2F5, a human HIV-1 gp41 membrane proximal external region (MPER)-specific BnAb, we previously demonstrated that a key obstacle to BnAb induction is clonal deletion of BnAb-expressing B cells. In this study of this model, we provide a proof-of-principle that robust serum neutralizing IgG responses can be induced from pre-existing, residual, self-reactive BnAb-expressing B cells in vivo using a structurally compatible gp41 MPER immunogen. Furthermore, in CD40L-deficient 2F5 KI mice, we demonstrate that these BnAb responses are elicited via a type II T-independent pathway, coinciding with expansion and activation of transitional splenic B cells specific for 2F5's nominal gp41 MPER-binding epitope (containing the 2F5 neutralization domain ELDKWA). In contrast, constitutive production of nonneutralizing serum IgGs in 2F5 KI mice is T dependent and originates from a subset of splenic mature B2 cells that have lost their ability to bind 2F5's gp41 MPER epitope. These results suggest that residual, mature B cells expressing autoreactive BnAbs, like 2F5 as BCR, may be limited in their ability to participate in T-dependent responses by purifying selection that selectively eliminates reactivity for neutralization epitope-containing/mimicked host Ags.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA. laurent.verkoczy@duke.edu
authors.forename: Laurent
authors.initials: L
authors.lastname: Verkoczy
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.forename: Hilary
authors.initials: H
authors.lastname: Bouton-Verville
authors.forename: Amanda
authors.initials: A
authors.lastname: Newman
authors.forename: Bradley
authors.initials: B
authors.lastname: Lockwood
authors.forename: Richard M
authors.initials: RM
authors.lastname: Scearce
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: S Moses
authors.initials: SM
authors.lastname: Dennison
authors.forename: Shi-Mao
authors.initials: SM
authors.lastname: Xia
authors.forename: Kwan-Ki
authors.initials: KK
authors.lastname: Hwang
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D000080908:Broadly Neutralizing Antibodies; D004797:Enzyme-Linked Immunosorbent Assay; D055879:Gene Knock-In Techniques; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009500:Neutralization Tests; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C558560:2F5 monoclonal antibody; D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41
references.citation: J Immunol. 2011 Oct 1;187(7):3785-97
references.pmid: 21908739
references.citation: J Virol. 1993 Nov;67(11):6642-7
references.pmid: 7692082
references.citation: J Immunol. 2008 Nov 1;181(9):5875-84
references.pmid: 18941176
references.citation: Nat Struct Mol Biol. 2010 Dec;17(12):1492-4
references.pmid: 21076400
references.citation: Cell. 2013 Mar 28;153(1):126-38
references.pmid: 23540694
references.citation: Curr Opin Immunol. 2011 Jun;23(3):383-90
references.pmid: 21524897
references.citation: J Exp Med. 1994 Nov 1;180(5):1889-900
references.pmid: 7964465
references.citation: J Virol. 2004 Oct;78(19):10724-37
references.pmid: 15367639
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8661-5
references.pmid: 1924327
references.citation: Nat Biotechnol. 2012 May 07;30(5):423-33
references.pmid: 22565972
references.citation: Cell. 1993 Feb 12;72(3):325-35
references.pmid: 8431943
references.citation: J Virol. 2009 Oct;83(19):10211-23
references.pmid: 19640992
references.citation: Immunol Res. 2000;21(2-3):89-102
references.pmid: 10852106
references.citation: Science. 2005 Jun 24;308(5730):1906-8
references.pmid: 15860590
references.citation: J Virol. 2008 Jan;82(1):115-25
references.pmid: 17942537
references.citation: AIDS Res Hum Retroviruses. 2001 Dec 10;17(18):1757-65
references.pmid: 11788027
references.citation: J Virol. 2005 Aug;79(16):10103-7
references.pmid: 16051803
references.citation: J Virol. 2001 Nov;75(22):10892-905
references.pmid: 11602729
references.citation: J Immunol. 2013 Aug 1;191(3):1260-75
references.pmid: 23825311
references.citation: J Virol. 2011 Nov;85(22):11725-31
references.pmid: 21917975
references.citation: J Immunol Methods. 2009 Oct 31;350(1-2):183-93
references.pmid: 19716372
references.citation: Curr Opin Immunol. 2009 Dec;21(6):626-33
references.pmid: 19800208
references.citation: J Virol. 2010 Feb;84(3):1439-52
references.pmid: 19939925
references.citation: Immunity. 2008 Jan;28(1):18-28
references.pmid: 18199415
references.citation: J Virol. 2004 Mar;78(6):3155-61
references.pmid: 14990736
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):17880-7
references.pmid: 20876137
references.citation: Trends Mol Med. 2011 Feb;17(2):108-16
references.pmid: 21112250
references.citation: J Virol. 2012 Mar;86(6):2930-41
references.pmid: 22238313
references.citation: PLoS One. 2009 Oct 06;4(10):e7215
references.pmid: 19806186
references.citation: Microbiol Mol Biol Rev. 2008 Mar;72(1):54-84, table of contents
references.pmid: 18322034
references.citation: Nat Rev Immunol. 2007 Aug;7(8):633-43
references.pmid: 17641666
references.citation: Immunity. 2003 Dec;19(6):837-47
references.pmid: 14670301
references.citation: Annu Rev Immunol. 1995;13:655-92
references.pmid: 7612238
references.citation: Hum Antibodies. 2005;14(3-4):59-67
references.pmid: 16720975
references.citation: Clin Immunol. 2003 Dec;109(3):278-87
references.pmid: 14697742
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):181-6
references.pmid: 20018688
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20234-9
references.pmid: 19906992
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3739-44
references.pmid: 18322015
references.citation: Immunity. 2005 Feb;22(2):163-73
references.pmid: 15723805
references.citation: J Immunol. 2007 Apr 1;178(7):4424-35
references.pmid: 17372000
references.citation: Annu Rev Immunol. 2010;28:413-44
references.pmid: 20192810
references.citation: Immunity. 2010 Oct 29;33(4):542-54
references.pmid: 21029964
references.citation: Annu Rev Immunol. 1992;10:489-518
references.pmid: 1590994
references.citation: PLoS One. 2011;6(11):e27824
references.pmid: 22140469
references.citation: Nat Commun. 2012 Apr 03;3:767
references.pmid: 22473011
references.citation: Trends Microbiol. 2012 Nov;20(11):532-9
references.pmid: 22981828
references.citation: Nature. 2013 Apr 25;496(7446):469-76
references.pmid: 23552890
references.citation: Science. 1996 Jun 14;272(5268):1649-52
references.pmid: 8658139
references.citation: Virology. 2006 Sep 30;353(2):268-82
references.pmid: 17039602
references.citation: J Exp Med. 2013 Feb 11;210(2):241-56
references.pmid: 23359068
references.citation: Immunol Rev. 2013 Jul;254(1):225-44
references.pmid: 23772623
references.citation: Curr Protoc Immunol. 2005 Jan;Chapter 12:Unit 12.11
references.pmid: 18432938