HIV-1 infection induces formation of a virological synapse wherein CD4, chemokine receptors, and cell-adhesion molecules such as lymphocyte function-associated antigen 1 (LFA-1) form localized domains on the cell surface. Studies show that LFA-1 on the surface of HIV-1 particles retains its adhesion function and enhances virus attachment to susceptible cells by binding its counterreceptor intercellular adhesion molecule 1 (ICAM-1). This virus–cell interaction augments virus infectivity by facilitating binding and entry events. In this study, we demonstrate that inhibition of the LFA-1/ICAM-1 interaction by a monoclonal antibody leads to decreased virus production and spread in association with increased apoptosis of HIV-infected primary T cells. The data indicate that the LFA-1/ICAM-1 interaction may limit apoptosis in HIV-1-infected T cells. This phenomenon appears similar to anoikis wherein epithelial cells are protected from apoptosis conferred by ligand-bound integrins. These results have implications for further understanding HIV pathogenesis and replication in peripheral compartments and lymphoid organs.
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References
1.
HoxieJA, FitzharrisTP, YoungbarPRet al.Nonrandom association of cellular antigens with HTLV-III virions. Hum Immunol, 1987; 18:39–52.
2.
ArthurLO, BessJWJr, SowderRC2ndet al.Cellular proteins bound to immunodeficiency viruses: Implications for pathogenesis and vaccines. Science, 1992; 258:1935–1938.
3.
MeerlooT, SheikhMA, BloemACet al.Host cell membrane proteins on human immunodeficiency virus type 1 after in vitro infection of H9 cells and blood mononuclear cells. An immuno-electron microscopic study. J Gen Virol, 1993; 74,Pt 1:129–135.
4.
OrentasRJ, HildrethJE. Association of host cell surface adhesion receptors and other membrane proteins with HIV and SIV. AIDS Res Hum Retroviruses, 1993; 9:1157–1165.
5.
SpearGT, LurainNS, ParkerCJet al.Host cell-derived complement control proteins CD55 and CD59 are incorporated into the virions of two unrelated enveloped viruses. Human T cell leukemia/lymphoma virus type I (HTLV-I) and human cytomegalovirus (HCMV)J Immunol, 1995; 155:4376–4381.
6.
GuoMM, HildrethJE. HIV acquires functional adhesion receptors from host cells. AIDS Res Hum Retroviruses, 1995; 11:1007–1013.
ButcherEC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell, 1991; 67:1033–1036.
9.
ButcherEC, PickerLJ. Lymphocyte homing and homeostasis. Science, 1996; 272:60–66.
10.
SpringerTA. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell, 1994; 76:301–314.
11.
DustinML, BivonaTG, PhilipsMR. Membranes as messengers in T cell adhesion signaling. Nat Immunol, 2004; 5:363–372.
12.
HildrethJE, OrentasRJ. Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation. Science, 1989; 244:1075–1078.
13.
HioeCE, HildrethJE, Zolla-PaznerS. Enhanced HIV type 1 neutralization by human anti-glycoprotein 120 monoclonal antibodies in the presence of monoclonal antibodies to lymphocyte function-associated molecule 1. AIDS Res Hum Retroviruses, 1999; 15:523–531.
14.
GoldingH, DimitrovDS, BlumenthalR. LFA-1 adhesion molecules are not involved in the early stages of HIV-1 env-mediated cell membrane fusion. AIDS Res Hum Retroviruses, 1992; 8:1593–1598.
15.
GomezMB, HildrethJE. Antibody to adhesion molecule LFA-1 enhances plasma neutralization of human immunodeficiency virus type 1. J Virol, 1995; 69:4628–4632.
16.
PantaleoG, ButiniL, GraziosiCet al.Human immunodeficiency virus (HIV) infection in CD4+ T lymphocytes genetically deficient in LFA-1: LFA-1 is required for HIV-mediated cell fusion but not for viral transmission. J Exp Med, 1991; 173:511–514.
17.
FortinJF, CantinR, LamontagneG, TremblayM. Host-derived ICAM-1 glycoproteins incorporated on human immunodeficiency virus type 1 are biologically active and enhance viral infectivity. J Virol, 1997; 71:3588–3596.
18.
ButiniL, De FougerollesAR, VaccarezzaMet al.Intercellular adhesion molecules (ICAM)-1 ICAM-2 and ICAM-3 function as counter-receptors for lymphocyte function-associated molecule 1 in human immunodeficiency virus-mediated syncytia formation. Eur J Immunol, 1994; 24:2191–2195.
19.
GruberMF, WebbDS, GerrardTLet al.Re-evaluation of the involvement of the adhesion molecules ICAM-1/LFA-1 in syncytia formation of HIV-1-infected subclones of a CEM T-cell leukemic line. AIDS Res Hum Retroviruses, 1991; 7:45–53.
20.
CantinR, FortinJF, LamontagneG, TremblayM. The acquisition of host-derived major histocompatibility complex class II glycoproteins by human immunodeficiency virus type 1 accelerates the process of virus entry and infection in human T-lymphoid cells. Blood, 1997; 90:1091–1100.
21.
FrankI, StoiberH, GodarSet al.Acquisition of host cell-surface-derived molecules by HIV-1. AIDS, 1996; 10:1611–1620.
22.
LallosLB, LaalS, HoxieJA, Zolla-PaznerS, BandresJC. Exclusion of HIV coreceptors CXCR4, CCR5, and CCR3 from the HIV envelope. AIDS Res Hum Retroviruses, 1999; 15:895–897.
23.
NguyenDH, HildrethJE. Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts. J Virol, 2000; 74:3264–3272.
24.
ArthosJ, CicalaC, MartinelliEet al.HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol, 2008; 9:301–309.
25.
MooreJP, KitchenSG, PugachP, ZackJA. The CCR5 and CXCR4 coreceptors–central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses, 2004; 20:111–126.
26.
PickerLJ. Immunopathogenesis of acute AIDS virus infection. Curr Opin Immunol, 2006; 18:399–405.
27.
van't WoutAB, KootstraNA, Mulder-KampingaGAet al.Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest, 1994; 94:2060–2067.
28.
ZhuT, MoH, WangNet al.Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science, 1993; 261:1179–1181.
GeginatJ, BossiG, BenderJR, PardiR. Anchorage dependence of mitogen-induced G1 to S transition in primary T lymphocytes. J Immunol, 1999; 162:5085–5093.
32.
RossettiG, CollingeM, BenderJR, MolteniR, PardiR. Integrin-dependent regulation of gene expression in leukocytes. Immunol Rev, 2002; 186:189–207.
33.
RytomaaM, MartinsLM, DownwardJ. Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr Biol, 1999; 9:1043–1046.
34.
StupackDG, PuenteXS, BoutsaboualoyS, StorgardCM, ChereshDA. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol, 2001; 155:459–470.
35.
BartzSR, EmermanM. Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8. J Virol, 1999; 73:1956–1963.
36.
CicalaC, ArthosJ, RubbertAet al.HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. Proc Natl Acad Sci USA, 2000; 97:1178–1183.
37.
Biard-PiechaczykM, Robert-HebmannV, RichardVet al.Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120)Virology, 2000; 268:329–344.
38.
RasolaA, GramagliaD, BoccaccioC, ComoglioPM. Apoptosis enhancement by the HIV-1 Nef protein. J Immunol, 2001; 166:81–88.
39.
VlahakisSR, Algeciras-SchimnichA, BouGet al.Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes. J Clin Invest, 2001; 107:207–215.
40.
KomotoS, KinomotoM, HorikoshiHet al.Ability to induce p53 and caspase-mediated apoptosis in primary CD4+ T cells is variable among primary isolates of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses, 2002; 18:435–446.
41.
de Oliveira PintoLM, GarciaS, LecoeurH, RappC, GougeonML. Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: Relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood, 2002; 99:1666–1675.
42.
de Oliveira PintoLM, LecoeurH, LedruEet al.Lack of control of T cell apoptosis under HAART. Influence of therapy regimen in vivo and in vitro. AIDS, 2002; 16:329–339.
43.
Algeciras-SchimnichA, VlahakisSR, Villasis-KeeverAet al.CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells. AIDS, 2002; 16:1467–1478.
44.
MuthumaniK, HwangDS, DesaiBMet al.HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. J Biol Chem, 2002; 277:37820–37831.
45.
NieZ, PhenixBN, LumJJet al.HIV-1 protease processes procaspase-8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation. Cell Death Differ, 2002; 9:1172–1184.
46.
HildrethJE, HoltV, AugustJT, PescovitzMD. Monoclonal antibodies against porcine LFA-1: Species cross-reactivity and functional effects of beta-subunit-specific antibodies. Mol Immunol, 1989; 26:883–895.
47.
PescovitzMD, LowmanMA, SachsDH. Expression of T-cell associated antigens by porcine natural killer cells. Immunology, 1988; 65:267–271.
48.
HildrethJE, AugustJT. The human lymphocyte function-associated (HLFA) antigen and a related macrophage differentiation antigen (HMac-1): Functional effects of subunit-specific monoclonal antibodies. J Immunol, 1985; 134:3272–3280.
49.
LawSK, GagnonJ, HildrethJEet al.The primary structure of the beta-subunit of the cell surface adhesion glycoproteins LFA-1, CR3 and p150,95 and its relationship to the fibronectin receptor. EMBO J, 1987; 6:915–919.
AdachiA, GendelmanHE, KoenigSet al.Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol, 1986; 59:284–291.
52.
O'DohertyU, SwiggardWJ, MalimMH. Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J Virol, 2000; 74:10074–10080.
53.
LosterK, SchulerC, HeidrichC, HorstkorteR, ReutterW. Quantification of cell-matrix and cell-cell adhesion using horseradish peroxidase. Anal Biochem, 1997; 244:96–102.
54.
DemirciG, LiXC. IL-2 and IL-15 exhibit opposing effects on Fas mediated apoptosis. Cell Mol Immunol, 2004; 1:123–128.
55.
DingZ, IssekutzTB, DowneyGP, WaddellTK. L-selectin stimulation enhances functional expression of surface CXCR4 in lymphocytes: Implications for cellular activation during adhesion and migration. Blood, 2003; 101:4245–4252.
56.
WeberKS, KlicksteinLB, WeberC. Specific activation of leukocyte beta2 integrins lymphocyte function-associated antigen-1 and Mac-1 by chemokines mediated by distinct pathways via the alpha subunit cytoplasmic domains. Mol Biol Cell, 1999; 10:861–873.
57.
CarrJM, HockingH, LiP, BurrellCJ. Rapid and efficient cell-to-cell transmission of human immunodeficiency virus infection from monocyte-derived macrophages to peripheral blood lymphocytes. Virology, 1999; 265:319–329.
58.
JollyC, MitarI, SattentauQJ. Adhesion molecule interactions facilitate human immunodeficiency virus type 1-induced virological synapse formation between T cells. J Virol, 2007; 81:13916–13921.
59.
BrenGD, TrushinSA, WhitmanJ, ShepardB, BadleyAD. HIV gp120 induces, NF-kappaB dependent, HIV replication that requires procaspase 8. PLoS One, 2009; 4:e4875.
60.
EmbretsonJ, ZupancicM, RibasJLet al.Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature, 1993; 362:359–362.
61.
KochetkovaM, KumarS, McCollSR. Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ, 2009; 16:664–673.
62.
RudnickaD, FeldmannJ, PorrotFet al.Simultaneous cell-to-cell transmission of human immunodeficiency virus to multiple targets through polysynapses. J Virol, 2009; 83:6234–6246.
63.
HoggN, PatzakI, WillenbrockF. The insider's guide to leukocyte integrin signalling and function. Nat Rev Immunol, 2011; 11:416–426.
64.
PiguetV, SattentauQ. Dangerous liaisons at the virological synapse. J Clin Invest, 2004; 114:605–610.
TardifMR, GilbertC, ThibaultS, FortinJF, TremblayMJ. LFA-1 antagonists as agents limiting human immunodeficiency virus type 1 infection and transmission and potentiating the effect of the fusion inhibitor T-20. Antimicrob Agents Chemother, 2009; 53:4656–4666.
MeredithJEJr, FazeliB, SchwartzMA. The extracellular matrix as a cell survival factor. Mol Biol Cell, 1993; 4:953–961.
70.
PullanS, WilsonJ, MetcalfeAet al.Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J Cell Sci, 1996; 109,Pt 3:631–642.
71.
KhwajaA, Rodriguez-VicianaP, WennstromS, WarnePH, DownwardJ. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J, 1997; 16:2783–2793.
72.
FarrellyN, LeeYJ, OliverJ, DiveC, StreuliCH. Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J Cell Biol, 1999; 144:1337–1348.
73.
AlmeidaEA, IlicD, HanQet al.Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol, 2000; 149:741–754.
SelliahN, FinkelTH. Biochemical mechanisms of HIV induced T cell apoptosis. Cell Death Differ, 2001; 8:127–136.
79.
AkariH, BourS, KaoS, AdachiA, StrebelK. The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor kappaB-dependent expression of antiapoptotic factors. J Exp Med, 2001; 194:1299–1311.
80.
ShostakLD, LudlowJ, FiskJet al.Roles of p53 and caspases in the induction of cell cycle arrest and apoptosis by HIV-1 vpr. Exp Cell Res, 1999; 251:156–165.
81.
VlahakisSR, Algeciras-SchimnichA, BouGet al.Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes. J Clin Invest, 2001; 107:207–215.
82.
BrooksPC, MontgomeryAM, RosenfeldMet al.Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell, 1994; 79:1157–1164.
StorgardCM, StupackDG, JonczykAet al.Decreased angiogenesis and arthritic disease in rabbits treated with an alphavbeta3 antagonist. J Clin Invest, 1999; 103:47–54.
85.
HynesRO, Hodivala-DilkeKM. Insights and questions arising from studies of a mouse model of Glanzmann thrombasthenia. Thromb Haemost, 1999; 82:481–485.
86.
GarridoM, MozosA, MartinezAet al.HIV-1 upregulates intercellular adhesion molecule-1 gene expression in lymphoid tissue of patients with chronic HIV-1 infection. J Acquir Immune Defic Syndr, 2007; 46:268–274.
87.
NgTT, GuntermannC, NyeKEet al.Adhesion co-receptor expression and intracellular signalling in HIV disease: Implications for immunotherapy. AIDS, 1995; 9:337–343.
88.
PantaleoG, GraziosiC, ButiniLet al.Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci USA, 1991; 88:9838–9842.
89.
KilbyJM. Human immunodeficiency virus pathogenesis: insights from studies of lymphoid cells and tissues. Clin Infect Dis, 2001; 33:873–884.
