Platelet activation suppresses HIV-1 infection of T cells

Retrovirology

Stefan Pöhlmann²  Jan Münch¹  Georg Behrens³  Annika Krämer-Kühl²  Miriam Kiene⁴  Niels Rahe-Meyer⁵  Kerstin Gnirß²  Theodros Solomon Tsegaye⁴ 

[1] Institute of Molecular Virology, University Hospital Ulm, Ulm, Germany;Infection Biology Unit, German Primate Center, Göttingen, Germany;Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany;Institute of Virology, Hannover Medical School, Hannover, Germany;Department of Anesthesiology and Intensive Care Unit, Hannover Medical School, Hannover, Germany

关键词: Entry;    Platelet;    CXCL4;    HIV-1;   

Others  :  1209131
DOI  :  10.1186/1742-4690-10-48

 received in 2012-11-02, accepted in 2013-04-22,  发布年份 2013

【 摘 要 】

Background

Platelets, anucleate cell fragments abundant in human blood, can capture HIV-1 and platelet counts have been associated with viral load and disease progression. However, the impact of platelets on HIV-1 infection of T cells is unclear.

Results

We found that platelets suppress HIV-1 spread in co-cultured T cells in a concentration-dependent manner. Platelets containing granules inhibited HIV-1 spread in T cells more efficiently than degranulated platelets, indicating that the granule content might exert antiviral activity. Indeed, supernatants from activated and thus degranulated platelets suppressed HIV-1 infection. Infection was inhibited at the stage of host cell entry and inhibition was independent of the viral strain or coreceptor tropism. In contrast, blockade of HIV-2 and SIV entry was less efficient. The chemokine CXCL4, a major component of platelet granules, blocked HIV-1 entry and neutralization of CXCL4 in platelet supernatants largely abrogated their anti-HIV-1 activity.

Conclusions

Release of CXCL4 by activated platelets inhibits HIV-1 infection of adjacent T cells at the stage of virus entry. The inhibitory activity of platelet-derived CXCL4 suggests a role of platelets in the defense against infection by HIV-1 and potentially other pathogens.

【 授权许可】

   
2013 Solomon Tsegaye et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]AIDS epidemic update 2009 http://www.unaids.org webcite
• [2]Lusso P: HIV and the chemokine system: 10 years later. EMBO J 2006, 25:447-456.
• [3]Ugolini S, Mondor I, Sattentau QJ: HIV-1 attachment: another look. Trends Microbiol 1999, 7:144-149.
• [4]Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR: DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000, 100:587-597.
• [5]van Montfort T, Nabatov AA, Geijtenbeek TB, Pollakis G, Paxton WA: Efficient capture of antibody neutralized HIV-1 by cells expressing DC-SIGN and transfer to CD4+ T lymphocytes. J Immunol 2007, 178:3177-3185.
• [6]Beck Z, Brown BK, Wieczorek L, Peachman KK, Matyas GR, Polonis VR, Rao M, Alving CR: Human erythrocytes selectively bind and enrich infectious HIV-1 virions. PLoS One 2009, 4:e8297.
• [7]Leslie M: Cell biology. Beyond clotting: the powers of platelets. Science 2010, 328:562-564.
• [8]McMorran BJ, Marshall VM, de Graaf C, Drysdale KE, Shabbar M, Smyth GK, Corbin JE, Alexander WS, Foote SJ: Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 2009, 323:797-800.
• [9]Passos AM, Treitinger A, Spada C: An overview of the mechanisms of HIV-related thrombocytopenia. Acta Haematol 2010, 124:13-18.
• [10]Rieg G, Yeaman M, Lail AE, Donfield SM, Gomperts ED, Daar ES: Platelet count is associated with plasma HIV type 1 RNA and disease progression. AIDS Res Hum Retroviruses 2007, 23:1257-1261.
• [11]Lee TH, Stromberg RR, Henrard D, Busch MP: Effect of platelet-associated virus on assays of HIV-1 in plasma. Science 1993, 262:1585-1586.
• [12]Lee TH, Stromberg RR, Heitman JW, Sawyer L, Hanson CV, Busch MP: Distribution of HIV type 1 (HIV-1) in blood components: detection and significance of high levels of HIV-1 associated with platelets. Transfusion 1998, 38:580-588.
• [13]Youssefian T, Drouin A, Masse JM, Guichard J, Cramer EM: Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation. Blood 2002, 99:4021-4029.
• [14]Boukour S, Masse JM, Benit L, Dubart-Kupperschmitt A, Cramer EM: Lentivirus degradation and DC-SIGN expression by human plateletes and megakaryocytes. J Thromb and Haemost 2006, 4:426-435.
• [15]Chaipan C, Soilleux EJ, Simpson P, Hofmann H, Gramberg T, Marzi A, Geier M, Stewart EA, Eisemann J, Steinkasserer A: DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J Virol 2006, 80:8951-8960.
• [16]Blair P, Flaumenhaft R: Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 2009, 23:177-189.
• [17]Auerbach DJ, Lin Y, Miao H, Cimbro R, Difiore MJ, Gianolini ME, Furci L, Biswas P, Fauci AS, Lusso P: Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor. Proc Natl Acad Sci U S A 2012, 109:9569-74.
• [18]Holme PA, Muller F, Solum NO, Brosstad F, Froland SS, Aukrust P: Enhanced activation of platelets with abnormal release of RANTES in human immunodeficiency virus type 1 infection. FASEB J 1998, 12:79-89.
• [19]Mayne E, Funderburg NT, Sieg SF, Asaad R, Kalinowska M, Rodriguez B, Schmaier AH, Stevens W, Lederman MM: Increased platelet and microparticle activation in HIV infection: upregulation of P-selectin and tissue factor expression. J Acquir Immune Defic Syndr 2012, 59:340-346.
• [20]Stone D, Liu Y, Shayakhmetov D, Li ZY, Ni S, Lieber A: Adenovirus-platelet interaction in blood causes virus sequestration to the reticuloendothelial system of the liver. J Virol 2007, 81:4866-4871.
• [21]Gear AR, Camerini D: Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation 2003, 10:335-350.
• [22]Slungaard A: Platelet factor 4: a chemokine enigma. Int J Biochem Cell Biol 2005, 37:1162-1167.
• [23]Nguyen DG, Hildreth JE: Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages. Eur J Immunol 2003, 33:483-493.
• [24]Pollicita M, Schols D, Aquaro S, Peumans WJ, Van Damme EJ, Perno CF, Balzarini J: Carbohydrate-binding agents (CBAs) inhibit HIV-1 infection in human primary monocyte-derived macrophages (MDMs) and efficiently prevent MDM-directed viral capture and subsequent transmission to CD4+ T lymphocytes. Virology 2008, 370:382-391.
• [25]Gramberg T, Hofmann H, Moller P, Lalor PF, Marzi A, Geier M, Krumbiegel M, Winkler T, Kirchhoff F, Adams DH: LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus. Virology 2005, 340:224-36.
• [26]Gramberg T, Soilleux E, Fisch T, Lalor PF, Hofmann H, Wheeldon S, Cotterill A, Wegele A, Winkler T, Adams DH: Interactions of LSECtin and DC-SIGN/DC-SIGNR with viral ligands: differential pH dependence, internalization and virion binding. Virology 2008, 373:189-201.
• [27]Means RE, Greenough T, Desrosiers RC: Neutralization sensitivity of cell culture-passaged simian immunodeficiency virus. J Virol 1997, 71:7895-7902.
• [28]Zander DM, Klinger M: The blood platelets contribution to innate host defense - what they have learned from their big brothers. Biotechnol J 2009, 4:914-926.
• [29]Bruisten S, van Gemen B, Koppelman M, Rasch M, van Strijp D, Schukkink R, Beyer R, Weigel H, Lens P, Huisman H: Detection of HIV-1 distribution in different blood fractions by two nucleic acid amplification assays. AIDS Res Hum Retroviruses 1993, 9:259-265.
• [30]Sabino EC, Gaburo N Jr, Leite JP, Viecili M, Rosenfeld LG: Platelets may affect detection and quantitation of HIV RNA in plasma samples with low viral loads. J Acquir Immune Defic Syndr 2004, 37:1432-1433.
• [31]Chaipan C, Steffen I, Tsegaye TS, Bertram S, Glowacka I, Kato Y, Schmokel J, Münch J, Simmons G, Gerardy-Schahn R: Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2. Retrovirology 2010, 7:47. BioMed Central Full Text
• [32]Massberg S, Konrad I, Schurzinger K, Lorenz M, Schneider S, Zohlnhoefer D, Hoppe K, Schiemann M, Kennerknecht E, Sauer S: Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 2006, 203:1221-1233.
• [33]Corrales-Medina VF, Simkins J, Chirinos JA, Serpa JA, Horstman LL, Jy W, Ahn YS: Increased levels of platelet microparticles in HIV-infected patients with good response to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2010, 54:217-218.
• [34]O’Brien M, Montenont E, Hu L, Nardi MA, Valdes V, Merolla M, Gettenberg G, Cavanagh K, Aberg JA, Bhardwaj N: Aspirin attenuates platelet activation and immune activation in HIV-infected subjects on antiretroviral therapy: a pilot study. J Acquir Immune Defic Syndr 2013. [Epub ahead of print]
• [35]Decrion AZ, Dichamp I, Varin A, Herbein G: HIV and inflammation. Curr HIV Res 2005, 3:243-259.
• [36]Jayachandran M, Brunn GJ, Karnicki K, Miller RS, Owen WG, Miller VM: In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk. J Appl Physiol 2007, 102:429-433.
• [37]von HP, Weber C: Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007, 100:27-40.
• [38]Schwartzkopff F, Grimm TA, Lankford CS, Fields K, Wang J, Brandt E, Clouse KA: Platelet factor 4 (CXCL4) facilitates human macrophage infection with HIV-1 and potentiates virus replication. Innate Immun 2009, 15:368-379.
• [39]Aslam R, Speck ER, Kim M, Crow AR, Bang KW, Nestel FP, Ni H, Lazarus AH, Freedman J, Semple JW: Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006, 107:637-641.
• [40]Platt EJ, Wehrly K, Kuhmann SE, Chesebro B, Kabat D: Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 1998, 72:2855-2864.
• [41]Schmitz G, Rothe G, Ruf A, Barlage S, Tschope D, Clemetson KJ, Goodall AH, Michelson AD, Nurden AT, Shankey TV: European working group on clinical cell analysis: consensus protocol for the flow cytometric characterisation of platelet function. Thromb Haemost 1998, 79:885-896.
• [42]Pöhlmann S, Leslie GJ, Edwards TG, Macfarlan T, Reeves JD, Hiebenthal-Millow K, Kirchhoff F, Baribaud F, Doms RW: DC-SIGN interactions with human immunodeficiency virus: virus binding and transfer are dissociable functions. J Virol 2001, 75:10523-10526.
• [43]Hiebenthal-Millow K, Pöhlmann S, Münch J, Kirchhoff F: Differential regulation of human immunodeficiency virus type 2 and simian immunodeficiency virus promoter activity. Virology 2004, 324:501-509.
• [44]Pöhlmann S, Stolte N, Münch J, Ten HP, Heeney JL, Stahl-Hennig C, Kirchhoff F: Co-receptor usage of BOB/GPR15 in addition to CCR5 has no significant effect on replication of simian immunodeficiency virus in vivo. J Infect Dis 1999, 180:1494-1502.
• [45]Connor RI, Chen BK, Choe S, Landau NR: Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 1995, 206:935-944.
• [46]Pierson TC, Zhou Y, Kieffer TL, Ruff CT, Buck C, Siliciano RF: Molecular characterization of preintegration latency in human immunodeficiency virus type 1 infection. J Virol 2002, 76:8518-8531.
• [47]Simmons G, Reeves JD, Grogan CC, Vandenberghe LH, Baribaud F, Whitbeck JC, Burke E, Buchmeier MJ, Soilleux EJ, Riley JL: DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology 2003, 305:115-123.
• [48]Papkalla A, Münch J, Otto C, Kirchhoff F: Nef enhances human immunodeficiency virus type 1 infectivity and replication independently of viral coreceptor tropism. J Virol 2002, 76:8455-8459.
• [49]Schindler M, Wurfl S, Benaroch P, Greenough TC, Daniels R, Easterbrook P, Brenner M, Münch J, Kirchhoff F: Down-modulation of mature major histocompatibility complex class II and up-regulation of invariant chain cell surface expression are well-conserved functions of human and simian immunodeficiency virus nef alleles. J Virol 2003, 77:10548-10556.