title: Immune adaptor ADAP in T cells regulates HIV-1 transcription and cell-cell viral spread via different co-receptors.
abstract: BACKGROUND
  Immune cell adaptor protein ADAP (adhesion and degranulation-promoting adaptor protein) mediates aspects of T-cell adhesion and proliferation. Despite this, a connection between ADAP and infection by the HIV-1 (human immunodeficiency virus-1) has not been explored.
  
  
  RESULTS
  In this paper, we show for the first time that ADAP and its binding to SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) regulate HIV-1 infection via two distinct mechanisms and co-receptors. siRNA down-regulation of ADAP, or expression of a mutant that is defective in associating to its binding partner SLP-76 (termed M12), inhibited the propagation of HIV-1 in T-cell lines and primary human T-cells. In one step, ADAP and its binding to SLP-76 were needed for the activation of NF-κB and its transcription of the HIV-1 long terminal repeat (LTR) in cooperation with ligation of co-receptor CD28, but not LFA-1. In a second step, the ADAP-SLP-76 module cooperated with LFA-1 to regulate conjugate formation between T-cells and dendritic cells or other T-cells as well as the development of the virological synapse (VS) and viral spread between immune cells.
  
  
  CONCLUSIONS
  These findings indicate that ADAP regulates two steps of HIV-1 infection cooperatively with two distinct receptors, and as such, serves as a new potential target in the blockade of HIV-1 infection.
authors.affiliation: The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai China. hongyanwang@sibcb.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Truus E M
authors.initials: TE
authors.lastname: Abbink
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Groppelli
authors.forename: Daina
authors.initials: D
authors.lastname: Lim
authors.forename: Youg Raj
authors.initials: YR
authors.lastname: Thaker
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Rongrong
authors.initials: R
authors.lastname: Zhai
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Lever
authors.forename: Clare
authors.initials: C
authors.lastname: Jolly
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002448:Cell Adhesion; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology*; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106957:FYB1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins
references.citation: J Exp Med. 2004 Jan 19;199(2):283-93
references.pmid: 14734528
references.citation: J Biol Chem. 1997 May 2;272(18):11674-7
references.pmid: 9115214
references.citation: Annu Rev Immunol. 2002;20:73-99
references.pmid: 11861598
references.citation: J Immunol. 2003 Jan 1;170(1):365-72
references.pmid: 12496421
references.citation: PLoS Pathog. 2011 Sep;7(9):e1002226
references.pmid: 21909273
references.citation: J Virol. 2008 Mar;82(6):3090-8
references.pmid: 18160437
references.citation: J Biol Chem. 2005 Jun 24;280(25):23576-83
references.pmid: 15849195
references.citation: Immunity. 2010 Apr 23;32(4):541-56
references.pmid: 20346707
references.citation: J Virol. 1998 Jul;72(7):6207-14
references.pmid: 9621091
references.citation: J Immunol. 2012 Mar 15;188(6):2769-77
references.pmid: 22323535
references.citation: Mol Cell Biol. 2000 Apr;20(8):2933-40
references.pmid: 10733597
references.citation: EMBO J. 2007 Jan 24;26(2):516-26
references.pmid: 17215865
references.citation: J Virol. 2010 Dec;84(23):12185-99
references.pmid: 20861257
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6684-9
references.pmid: 18443296
references.citation: Science. 2003 May 23;300(5623):1295-7
references.pmid: 12730499
references.citation: Science. 1988 Mar 11;239(4845):1299-302
references.pmid: 2830675
references.citation: Nat Immunol. 2003 Feb;4(2):110-6
references.pmid: 12555096
references.citation: Science. 2007 May 4;316(5825):754-8
references.pmid: 17478723
references.citation: Nat Immunol. 2011 Jul 19;12(8):683-5
references.pmid: 21772275
references.citation: J Virol. 2005 Nov;79(21):13714-24
references.pmid: 16227291
references.citation: Bioessays. 2004 Jan;26(1):61-7
references.pmid: 14696041
references.citation: Nat Immunol. 2003 Aug;4(8):741-8
references.pmid: 12845325
references.citation: Adv Immunol. 2001;79:93-128
references.pmid: 11680012
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3862-6
references.pmid: 8171003
references.citation: J Virol. 2002 Feb;76(3):1004-14
references.pmid: 11773376
references.citation: Mol Cell Biol. 2007 Oct;27(19):6863-75
references.pmid: 17646386
references.citation: Science. 2009 Mar 27;323(5922):1743-7
references.pmid: 19325119
references.citation: J Biol Chem. 2010 Apr 9;285(15):11100-5
references.pmid: 20164171
references.citation: J Cell Biol. 2000 Apr 3;149(1):181-94
references.pmid: 10747096
references.citation: J Virol. 2009 Nov;83(21):11341-55
references.pmid: 19710135
references.citation: Trends Cell Biol. 2008 Oct;18(10):486-93
references.pmid: 18760924
references.citation: Nat Rev Microbiol. 2008 Nov;6(11):815-26
references.pmid: 18923409
references.citation: J Exp Med. 2004 Sep 20;200(6):749-59
references.pmid: 15365096
references.citation: EMBO J. 1990 May;9(5):1551-60
references.pmid: 2184033
references.citation: Nature. 1987 Apr 16-22;326(6114):711-3
references.pmid: 3031512
references.citation: J Biol Chem. 2011 Aug 26;286(34):29663-70
references.pmid: 21669874
references.citation: J Exp Med. 2004 Nov 15;200(10):1279-88
references.pmid: 15545354
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3394-9
references.pmid: 10716728
references.citation: Mol Cell Biol. 2003 Oct;23(19):7068-81
references.pmid: 12972622
references.citation: J Virol. 2009 May;83(9):4195-204
references.pmid: 19211748
references.citation: J Virol. 1992 Jan;66(1):139-49
references.pmid: 1727476
references.citation: Blood. 2007 Jan 1;109(1):168-75
references.pmid: 16973965
references.citation: J Biol Chem. 1998 Mar 27;273(13):7431-40
references.pmid: 9516441
references.citation: Blood. 2008 May 1;111(9):4660-3
references.pmid: 18296630
references.citation: Nat Immunol. 2003 Apr;4(4):366-74
references.pmid: 12652296
references.citation: Annu Rev Immunol. 2006;24:227-55
references.pmid: 16551249
references.citation: J Virol. 2010 Apr;84(7):3516-27
references.pmid: 20089656
references.citation: J Virol. 2007 Nov;81(22):12582-95
references.pmid: 17728240
references.citation: Mol Cell Biol. 2006 Oct;26(19):7130-44
references.pmid: 16980616
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12436-41
references.pmid: 19617540
references.citation: Retrovirology. 2006 Nov 01;3:75
references.pmid: 17078873
references.citation: Immunity. 1997 Mar;6(3):235-44
references.pmid: 9075924
references.citation: PLoS Pathog. 2012;8(8):e1002861
references.pmid: 22876188
references.citation: Nat Cell Biol. 2008 Feb;10(2):211-9
references.pmid: 18193035
references.citation: Nat Rev Immunol. 2002 Oct;2(10):725-34
references.pmid: 12360211
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12955-60
references.pmid: 14569007
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7493-8
references.pmid: 9207119
references.citation: AIDS Res Hum Retroviruses. 1998 Oct;14 Suppl 3:S247-54
references.pmid: 9814951
references.citation: J Exp Med. 2004 Oct 18;200(8):1063-74
references.pmid: 15477347