title: HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+ T Lymphocytes.
abstract: Leukocyte recirculation between blood and lymphoid tissues is required for the generation and maintenance of immune responses against pathogens and is crucially controlled by the L-selectin (CD62L) leukocyte homing receptor. CD62L has adhesion and signaling functions and initiates the capture and rolling on the vascular endothelium of cells entering peripheral lymph nodes. This study reveals that CD62L is strongly downregulated on primary CD4(+) T lymphocytes upon infection with human immunodeficiency virus type 1 (HIV-1). Reduced cell surface CD62L expression was attributable to the Nef and Vpu viral proteins and not due to increased shedding via matrix metalloproteases. Both Nef and Vpu associated with and sequestered CD62L in perinuclear compartments, thereby impeding CD62L transport to the plasma membrane. In addition, Nef decreased total CD62L protein levels. Importantly, infection with wild-type, but not Nef- and Vpu-deficient, HIV-1 inhibited the capacity of primary CD4(+) T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1 infection impaired the signaling pathways and costimulatory signals triggered in primary CD4(+) T cells by CD62L ligation. We propose that HIV-1 dysregulates CD62L expression to interfere with the trafficking and activation of infected T cells. Altogether, this novel HIV-1 function could contribute to virus dissemination and evasion of host immune responses.
  
  
  OBJECTIVE
  L-selectin (CD62L) is an adhesion molecule that mediates the first steps of leukocyte homing to peripheral lymph nodes, thus crucially controlling the initiation and maintenance of immune responses to pathogens. Here, we report that CD62L is downmodulated on the surfaces of HIV-1-infected T cells through the activities of two viral proteins, Nef and Vpu, that prevent newly synthesized CD62L molecules from reaching the plasma membrane. We provide evidence that CD62L downregulation on HIV-1-infected primary T cells results in impaired adhesion and signaling functions upon CD62L triggering. Removal of cell surface CD62L may predictably keep HIV-1-infected cells away from lymph nodes, the privileged sites of both viral replication and immune response activation, with important consequences, such as systemic viral spread and evasion of host immune surveillance. Altogether, we propose that Nef- and Vpu-mediated subversion of CD62L function could represent a novel determinant of HIV-1 pathogenesis.
authors.affiliation: Laboratory of Immunoinfectivology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Lia
authors.initials: L
authors.lastname: Vassena
authors.affiliation: Laboratory of Immunoinfectivology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Giuliani
authors.affiliation: Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Herwig
authors.initials: H
authors.lastname: Koppensteiner
authors.affiliation: Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bolduan
authors.affiliation: Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany Institute of Medical Virology and Epidemiology of Viral Diseases, University Clinic Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
authors.affiliation: Laboratory of Immunoinfectivology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy doria@uniroma2.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Doria
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D019041:L-Selectin / Q000378:metabolism*; D008213:Lymphocyte Activation; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D054298:Human Immunodeficiency Virus Proteins; D019041:L-Selectin; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
references.citation: Retrovirology. 2010;7:114
references.pmid: 21176220
references.citation: J Exp Med. 1996 Feb 1;183(2):589-98
references.pmid: 8627170
references.citation: Cell Host Microbe. 2010 Jul 22;8(1):55-67
references.pmid: 20638642
references.citation: J Immunol. 1997 Oct 1;159(7):3498-507
references.pmid: 9317149
references.citation: Nature. 2012 Oct 11;490(7419):283-7
references.pmid: 22854780
references.citation: Microcirculation. 2003 Jun;10(3-4):351-8
references.pmid: 12851651
references.citation: Virology. 2011 Feb 20;410(2):316-26
references.pmid: 21176845
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15376-81
references.pmid: 8986819
references.citation: Int J Biochem Cell Biol. 2013 Mar;45(3):550-5
references.pmid: 23299028
references.citation: J Immunol. 1999 Sep 15;163(6):3539-48
references.pmid: 10477629
references.citation: PLoS One. 2010;5(2):e9344
references.pmid: 20179761
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9763-8
references.pmid: 10449768
references.citation: FASEB J. 2013 Jun;27(6):2440-50
references.pmid: 23395909
references.citation: J Immunol. 2002 Aug 15;169(4):2034-43
references.pmid: 12165530
references.citation: Virology. 1997 Feb 17;228(2):141-52
references.pmid: 9123820
references.citation: J Virol. 2010 Mar;84(5):2282-93
references.pmid: 20015995
references.citation: J Virol. 2012 Apr;86(8):4496-504
references.pmid: 22301152
references.citation: FASEB J. 2004 Dec;18(15):1851-61
references.pmid: 15576488
references.citation: J Virol. 2014 Dec;88(24):14241-57
references.pmid: 25275127
references.citation: AIDS. 2000 Nov 10;14(16):2429-36
references.pmid: 11101052
references.citation: Cell Logist. 2011 May;1(3):90-102
references.pmid: 21922073
references.citation: PLoS One. 2014;9(10):e110719
references.pmid: 25330112
references.citation: J Exp Med. 2003 Nov 3;198(9):1323-35
references.pmid: 14597735
references.citation: J Immunol Methods. 1992 Nov 25;156(1):115-23
references.pmid: 1385536
references.citation: J Leukoc Biol. 2009 Nov;86(5):1171-8
references.pmid: 19641037
references.citation: Blood. 2004 Feb 15;103(4):1218-21
references.pmid: 14576059
references.citation: Nature. 1991 Feb 21;349(6311):691-4
references.pmid: 1705015
references.citation: Clin Exp Immunol. 1999 Aug;117(2):331-4
references.pmid: 10444267
references.citation: Cell Rep. 2014 Jun 26;7(6):2019-30
references.pmid: 24910430
references.citation: Immunity. 1994 Jul;1(4):247-60
references.pmid: 7534203
references.citation: AIDS Res Hum Retroviruses. 1999 Jan 20;15(2):161-71
references.pmid: 10029248
references.citation: Mol Cell Proteomics. 2014 Jul;13(7):1676-89
references.pmid: 24797426
references.citation: Microbiol Mol Biol Rev. 2006 Jun;70(2):548-63
references.pmid: 16760313
references.citation: J Immunol. 1995 May 1;154(9):4351-62
references.pmid: 7536769
references.citation: PLoS One. 2011;6(7):e22560
references.pmid: 21829468
references.citation: J Virol. 2005 May;79(9):5489-98
references.pmid: 15827163
references.citation: J Clin Immunol. 2001 Jul;21(4):286-92
references.pmid: 11506199
references.citation: Clin Diagn Lab Immunol. 1998 Jul;5(4):583-7
references.pmid: 9665971
references.citation: Eur J Cell Biol. 2012 Apr;91(4):257-64
references.pmid: 21546114
references.citation: J Immunol. 1992 Mar 15;148(6):1771-6
references.pmid: 1371790
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18541-6
references.pmid: 23093676
references.citation: J Infect Dis. 2001 Jul 1;184(1):93-7
references.pmid: 11398115
references.citation: J Immunol. 2008 Jan 1;180(1):198-206
references.pmid: 18097020
references.citation: J Virol. 2013 Jun;87(12):7160-5
references.pmid: 23552418
references.citation: Trends Mol Med. 2007 Nov;13(11):449-59
references.pmid: 18029231
references.citation: Science. 2014 Mar 14;343(6176):1221-8
references.pmid: 24557838
references.citation: J Exp Med. 1996 Oct 1;184(4):1343-8
references.pmid: 8879206
references.citation: Inflammation. 2003 Oct;27(5):265-80
references.pmid: 14635784
references.citation: J Gen Virol. 2007 Jan;88(Pt 1):242-50
references.pmid: 17170457