Journal of Thrombosis and Thrombolysis

, Volume 33, Issue 2, pp 160–172 | Cite as

Human cytomegalovirus infection and atherothrombosis

  • Milan Popović
  • Katarina Smiljanić
  • Branislava Dobutović
  • Tatiana Syrovets
  • Thomas Simmet
  • Esma R. Isenović
Article

Abstract

Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs). HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intima-media thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving nuclear factor κB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages. As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation.

Keywords

HCMV Coagulation Vascular inflammation Atherosclerosis 

Abbreviations

Ab

Antibody

Akt

Serine/threonine protein kinase

aPL

Antiphospholipid

ECs

Endothelial cells

HCMV

Human cytomegalovirus

EGFR

Epidermal growth factor receptor

HSV-1

Herpes simplex virus 1 (human herpes virus 1)

HSV-2

Herpes simplex virus 2 (human herpes virus 2)

IL-1α

Interleukin-1α

ICAM-1

Intercellular adhesion molecule-1

MAPK

Mitogen activated protein kinase

M-CSF

Macrophage colony-stimulating factor

NF-κB

Nuclear factor-κB

PI3K

Phosphatidylinositol 3-kinase

PDGFR

Platelet-derived growth factor receptor

PDGFR-β

Platelet-derived growth factor receptor-β

proPL

Procoagulant phospholipid

Sp1

Specificity protein 1

SMCs

Smooth muscle cells

VCAM-1

Vascular cell adhesion molecule-1

VSMCs

Vascular smooth muscle cells

References

  1. 1.
    Bombeli T, Mueller M, Haeberli A (1997) Anticoagulant properties of the vascular endothelium. Thromb Haemost 77:408–423PubMedGoogle Scholar
  2. 2.
    Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMedGoogle Scholar
  3. 3.
    Rosenberg RD, Rosenberg JS (1984) Natural anticoagulant mechanisms. J Clin Invest 76:1–5CrossRefGoogle Scholar
  4. 4.
    Stamler JS, Singel DJ, Loscalzo J (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258:1898–1902PubMedCrossRefGoogle Scholar
  5. 5.
    Zimmerman GA, Whatley RE, Benson DE, Prescott SM (1990) Endothelial cells for studies of platelet-activating factor and arachidonate metabolites. Methods Enzymol 187:520–535PubMedCrossRefGoogle Scholar
  6. 6.
    Fantone CJ, Ward PA (1982) Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol 107:395–418PubMedGoogle Scholar
  7. 7.
    Touyz RM (2003) Reactive oxygen species in vascular biology: role in arterial hypertension. Expert Rev Cardiovasc Ther 1:91–106PubMedCrossRefGoogle Scholar
  8. 8.
    Lubrano V, Di Cecco P, Zucchelli GC (2006) Role of superoxide dismutase in vascular inflammation and in coronary artery disease. Clin Exp Med 6:84–88PubMedCrossRefGoogle Scholar
  9. 9.
    Coughlin SR (1999) How the protease thrombin talks to cells. Proc Natl Acad Sci USA 96:11023–11027PubMedCrossRefGoogle Scholar
  10. 10.
    Roth GJ (1992) Platelets and blood vessels: the adhesion event. Immunol Today 13:100–105PubMedCrossRefGoogle Scholar
  11. 11.
    Butcher EC (1991) Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67:1033–1036PubMedCrossRefGoogle Scholar
  12. 12.
    Ebnet K, Vestweber D (1999) Molecular mechanism that control leukocyte extravasation: the selectins and chemokines. Histochem Cell Biol 112:1–23PubMedCrossRefGoogle Scholar
  13. 13.
    Nawroth PP, Stern DM (1985) An endothelial cell procogaulant pathway. J Cell Biochem 28:253–264PubMedCrossRefGoogle Scholar
  14. 14.
    Stern DM, Carpenter B, Nawroth PP (1986) Endothelium and the regulation of coagulation. Pathol Immunopathol Res 5:29–36PubMedCrossRefGoogle Scholar
  15. 15.
    Springer TA (1990) Adhesion receptors of the immune system. Nature 346:425–434PubMedCrossRefGoogle Scholar
  16. 16.
    Bevilacqua MP, Nelson RM, Mannori G, Cecconi O (1994) Endothelial-leukocyte adhesion molecules in human disease. Annu Rev Med 45:361–378PubMedCrossRefGoogle Scholar
  17. 17.
    Reeves M, Sinclair J (2008) Aspects of human cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol 325:297–313PubMedCrossRefGoogle Scholar
  18. 18.
    Vanegas F, Montalvo RD, Alvarez OA, Donelson SS, Lee M (2000) Massive upper gastrointestinal hemorrhage due to cytomegalovirus infection in two patients with acquired immunodeficiency syndrome. South Med J 93:235–238PubMedGoogle Scholar
  19. 19.
    Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, Robinson CA, Stempien MJ (2002) A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis; Valganciclovir Study Group. N Engl J Med 346:1119–1126PubMedCrossRefGoogle Scholar
  20. 20.
    Bissinger AL, Sinzger C, Kaiserling E, Jahn G (2002) Human cytomegalovirus as a direct pathogen: correlation of multiorgan involvement and cell distribution with clinical and pathological findings in a case of congenital inclusion disease. J Med Virol 67:200–206PubMedCrossRefGoogle Scholar
  21. 21.
    Snydman DR (2008) Persistent clinical impact of cytomegalovirus in organ transplantation. Clin Infect Dis 47:883–884PubMedCrossRefGoogle Scholar
  22. 22.
    Kotton CN (2010) Management of cytomegalovirus infection in solid organ transplantation. Nat Rev Nephrol 6:711–721PubMedCrossRefGoogle Scholar
  23. 23.
    Morris MI, Fischer SA, Ison MG (2010) Infections transmitted by transplantation. Infect Dis Clin North Am 24:497–514PubMedCrossRefGoogle Scholar
  24. 24.
    Epstein SE, Zhu J, Burnett MS, Zhou YF, Vercellotti G, Hajjar D (2000) Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry. Arterioscler Thromb Vasc Biol 20:1417–1420PubMedCrossRefGoogle Scholar
  25. 25.
    Streblow DN, Orloff SL, Nelson JA (2001) Do pathogens accelerate atherosclerosis? J Nutr 131:2798S–2804SPubMedGoogle Scholar
  26. 26.
    Yi L, Wang DX, Feng ZJ (2008) Detection of human cytomegalovirus in atherosclerotic carotid arteries in humans. J Formos Med Assoc 107:774–781PubMedCrossRefGoogle Scholar
  27. 27.
    Xenaki E, Hassoulas J, Apostolakis S, Sourvinos G, Spandidos DA (2009) Detection of cytomegalovirus in atherosclerotic plaques and nonatherosclerotic arteries. Angiology 60:504–508PubMedCrossRefGoogle Scholar
  28. 28.
    Fish KN, Stenglein SG, Ibanez C, Nelson JA (1995) Cytomegalovirus persistence in macrophages and endothelial cells. Scand J Infect Dis Suppl 99:34–40PubMedGoogle Scholar
  29. 29.
    Fish KN, Soderberg-Naucler C, Mills LK, Stenglein S, Nelson JA (1998) Human cytomegalovirus persistently infects aortic endothelial cells. J Virol 72:5661–5668PubMedGoogle Scholar
  30. 30.
    Jarvis MA, Nelson JA (2002) Human cytomegalovirus persistence and latency in endothelial cells and macrophages. Curr Opin Microbiol 5:403–407PubMedCrossRefGoogle Scholar
  31. 31.
    Sinzger C, Grefte A, Plachter B, Gouw AS, The TH, Jahn G (1995) Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues. J Gen Virol 76:741–750PubMedCrossRefGoogle Scholar
  32. 32.
    Sinzger C, Digel M, Jahn G (2008) Cytomegalovirus cell tropism. Curr Top Microbiol Immunol 325:63–83PubMedCrossRefGoogle Scholar
  33. 33.
    Stanton RJ, Baluchova K, Dargan DJ, Cunningham C, Sheehy O, Seirafian S, McSharry BP, Neale ML, Davies JA, Tomasec P, Davison AJ, Wilkinson GW (2010) Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication. J Clin Invest 120:3191–3208PubMedCrossRefGoogle Scholar
  34. 34.
    Compton T, Nepomuceno RR, Nowlin DM (1992) Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology 191:387–395PubMedCrossRefGoogle Scholar
  35. 35.
    Ryckman BJ, Jarvis MA, Drummond DD, Nelson JA, Johnson DC (2006) Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol 80:710–722PubMedCrossRefGoogle Scholar
  36. 36.
    Mach M, Kropff B, Dal Monte P, Britt W (2000) Complex formation by human cytomegalovirus glycoproteins M (gpUL100) and N (gpUL73). J Virol 74:11881–11892PubMedCrossRefGoogle Scholar
  37. 37.
    Varnum SM, Streblow DN, Monroe ME, Smith P, Auberry KJ, Pasa-Tolic L, Wang D, Camp DG II, Rodland K, Wiley S, Britt W, Shenk T, Smith RD, Nelson JA (2004) Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J Virol 78:10960–10966PubMedCrossRefGoogle Scholar
  38. 38.
    Wang D, Shenk T (2005) Human cytomegalovirus UL131 open reading frame is required for epithelial cell tropism. J Virol 79:10330–10338PubMedCrossRefGoogle Scholar
  39. 39.
    Dengler TJ, Raftery MJ, Werle M, Zimmermann R, Schönrich G (2000) Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1beta. Transplantation 69:1160–1168PubMedCrossRefGoogle Scholar
  40. 40.
    Maisch T, Kropff B, Sinzger C, Mach M (2002) Upregulation of CD40 expression on endothelial cells infected with human cytomegalovirus. J Virol 76:12803–12812PubMedCrossRefGoogle Scholar
  41. 41.
    Gerna G, Percivalle E, Baldanti F, Sozzani S, Lanzarini P, Genini E, Lilleri D, Revello MG (2000) Human cytomegalovirus replicates abortively in polymorphonuclear leukocytes after transfer from infected endothelial cells via transient microfusion events. J Virol 74:5629–5638PubMedCrossRefGoogle Scholar
  42. 42.
    Rahbar A, Söderberg-Nauclér C (2005) Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation. J Virol 79:2211–2220PubMedCrossRefGoogle Scholar
  43. 43.
    Bentz GL, Yurochko AD (2008) Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. Proc Natl Acad Sci USA 105:5531–5536PubMedCrossRefGoogle Scholar
  44. 44.
    Wang X, Huong SM, Chiu ML, Raab-Traub N, Huang ES (2003) Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424:456–461PubMedCrossRefGoogle Scholar
  45. 45.
    Beutler T, Höflich C, Stevens PA, Krüger DH, Prösch S (2003) Downregulation of the epidermal growth factor receptor by human cytomegalovirus infection in human fetal lung fibroblasts. Am J Respir Cell Mol Biol 28:86–94PubMedCrossRefGoogle Scholar
  46. 46.
    Isaacson MK, Feire AL, Compton T (2007) Epidermal growth factor receptor is not required for human cytomegalovirus entry or signaling. J Virol 81:6241–6247PubMedCrossRefGoogle Scholar
  47. 47.
    Zhou YF, Yu ZX, Wanishsawad C, Shou M, Epstein SE (1999) The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor. Biochem Biophys Res Commun 256:608–613PubMedCrossRefGoogle Scholar
  48. 48.
    Reinhardt B, Mertens T, Mayr-Beyrle U, Frank H, Lüske A, Schierling K, Waltenberger J (2005) HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF beta-receptor. Cardiovasc Res 67:151–160PubMedCrossRefGoogle Scholar
  49. 49.
    Hajjar DP (1986) Herpesvirus infection prevents activation of cytoplasmic cholesteryl esterase in arterial smooth muscle cells. J Biol Chem 261:7611–7614PubMedGoogle Scholar
  50. 50.
    Zhou YF, Guetta E, Yu ZX, Finkel T, Epstein SE (1996) Human cytomegalovirus increases modified low density lipoprotein uptake and scavenger receptor mRNA expression in vascular smooth muscle cells. J Clin Invest 98:2129–2138PubMedCrossRefGoogle Scholar
  51. 51.
    Andreoni KA, Wang X, Huang SM, Huang ES (2002) Human cytomegalovirus hyperimmune globulin not only neutralizes HCMV infectivity, but also inhibits HCMV-induced intracellular NF-kappaB, Sp1, and PI3-K signaling pathways. J Med Virol 67:33–40PubMedCrossRefGoogle Scholar
  52. 52.
    Bentz GL, Jarquin-Pardo M, Chan G, Smith MS, Sinzger C, Yurochko AD (2006) Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV. J Virol 80:11539–11555PubMedCrossRefGoogle Scholar
  53. 53.
    Schäfer P, Tenschert W, Cremaschi L, Schröter M, Gutensohn K, Laufs R (2000) Cytomegalovirus cultured from different major leukocyte subpopulations: association with clinical features in CMV immunoglobulin G-positive renal allograft recipients. J Med Virol 61:488–496PubMedCrossRefGoogle Scholar
  54. 54.
    Dargan DJ, Douglas E, Cunningham C, Jamieson F, Stanton RJ, Baluchova K, McSharry BP, Tomasec P, Emery VC, Percivalle E, Sarasini A, Gerna G, Wilkinson GW, Davison AJ (2010) Sequential mutations associated with adaptation of human cytomegalovirus to growth in cell culture. J Gen Virol 91:1535–1546PubMedCrossRefGoogle Scholar
  55. 55.
    Prichard MN, Penfold ME, Duke GM, Spaete RR, Kemble GW (2001) A review of genetic differences between limited and extensively passaged human cytomegalovirus strains. Rev Med Virol 11:191–200PubMedCrossRefGoogle Scholar
  56. 56.
    Bradley AJ, Lurain NS, Ghazal P, Trivedi U, Cunningham C, Baluchova K, Gatherer D, Wilkinson GW, Dargan DJ, Davison AJ (2009) High-throughput sequence analysis of variants of human cytomegalovirus strains Towne and AD169. J Gen Virol 90:2375–2380PubMedCrossRefGoogle Scholar
  57. 57.
    van Dam-Mieras MC, Bruggeman CA, Muller AD, Debie WH, Zwaal RF (1987) Induction of endothelial cell procoagulant activity by cytomegalovirus infection. Thromb Res 47:69–75PubMedCrossRefGoogle Scholar
  58. 58.
    Visser MR, Tracy PB, Vercellotti GM, Goodman JL, White JG, Jacob HS (1988) Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium. Proc Natl Acad Sci USA 85:8227–8230PubMedCrossRefGoogle Scholar
  59. 59.
    van Dam-Mieras MC, Muller AD, van Hinsbergh VW, Mullers WJ, Bomans PH, Bruggeman CA (1992) The procoagulant response of cytomegalovirus infected endothelial cells. Thromb Haemost 88:364–370Google Scholar
  60. 60.
    Sutherland MR, Raynor CM, Leenknegt H, Wright JF, Pryzdial ELG (1997) Coagulation initiated on herpesviruses. Proc Natl Acad Sci USA 94:13510–13514PubMedCrossRefGoogle Scholar
  61. 61.
    Livingston JR, Sutherland MR, Friedman HM, Pryzdial EL (2006) Herpes simplex virus type 1-encoded glycoprotein C contributes to direct coagulation factor X-virus binding. Biochem J 393:529–535PubMedCrossRefGoogle Scholar
  62. 62.
    Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation. Circulation 109:2698–2704PubMedCrossRefGoogle Scholar
  63. 63.
    Etingin OR, Silverstein RL, Friedman HM, Hajjar DP (1990) Viral activation of the coagulation cascade: molecular interactions at the surface of infected endothelial cells. Cell 61:657–662PubMedCrossRefGoogle Scholar
  64. 64.
    Melnick JL, Adam E, DeBakey ME (1990) Possible role of cytomegalovirus in atherogenesis. JAMA 263:2204–2207PubMedCrossRefGoogle Scholar
  65. 65.
    McSorley J, Shapiro L, Brownstein MH, Hsu KC (1974) Herpes simplex and varicella-zoster: comparative histopathology of 77 cases. Int J Dermatol 13:69–75PubMedCrossRefGoogle Scholar
  66. 66.
    Phinney PR, Fligiel S, Bryson YJ, Porter DD (1982) Necrotizing vasculitis in a case of disseminated neonatal herpes simplex infection. Arch Pathol Lab Med 106:64–67PubMedGoogle Scholar
  67. 67.
    Hruban RH, Wu T-C, Beschomer WE, Cameron DE, Ambinder R, Baumgartner WA, Reitz BA, Hutchins GM (1990) Cytomegalovirus nucleic acids in allografted hearts. Hum Pathol 21:981–982PubMedCrossRefGoogle Scholar
  68. 68.
    Foegh ML (1990) Chronic rejection—graft arteriosclerosis. Transplant Proc 22:119–122PubMedGoogle Scholar
  69. 69.
    Wu TC, Hruban RH, Ambinder RF, Pizzomo M, Cameron DE, Baumgartner WA, Reitz BA, Hayward GS, Hutchins GM (1992) Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts. Am J Pathol 140:739–747PubMedGoogle Scholar
  70. 70.
    Fabricant CG, Fabricant J, Litrenta MM, Minick CR (1978) Virus induced atherosclerosis. J Exp Med 148:335–340PubMedCrossRefGoogle Scholar
  71. 71.
    Fabricant CG, Fabricant J, Minick CR, Litrenta MM (1983) Herpesvirus induced atherosclerosis in chickens. Fed Proc 42:2476–2479PubMedGoogle Scholar
  72. 72.
    Span AHM, Grauls G, Bosman F, Vanboven CPA, Bruggeman CA (1992) Cytomegalovirus infection induces vascular injury in the rat. Atherosclerosis 93:41–52PubMedCrossRefGoogle Scholar
  73. 73.
    Pryzdial EL, Wright JF (1994) Prothrombinase assembly on an enveloped virus: evidence that the cytomegalovirus surface contains procoagulant phospholipid. Blood 84:3749–3757PubMedGoogle Scholar
  74. 74.
    Rosenberg RD (1985) Role of heparin and heparinlike molecules in thrombosis and atherosclerosis. Biochemistry 24:6723–6729PubMedCrossRefGoogle Scholar
  75. 75.
    Rux AH, Lou H, Lambris JD, Friedman HM, Eisenberg RJ, Cohen GH (2005) Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate, and complement component C3b. Virology 294:324–332CrossRefGoogle Scholar
  76. 76.
    Etingin OR, Silverstein RL, Hajjar DP (1991) Identification of a monocyte receptor on herpesvirus-infected endothelial cells. Proc Natl Acad Sci USA 88:7200–7203PubMedCrossRefGoogle Scholar
  77. 77.
    Popović M, Paskas S, Zivković M, Burysek L, Laumonnier Y (2010) Human cytomegalovirus increases HUVEC sensitivity to thrombin and modulates expression of thrombin receptors. J Thromb Thrombolysis 30:164–171PubMedCrossRefGoogle Scholar
  78. 78.
    Inacio C, Hillaire S, Valla D, Denninger MH, Casadevall N, Erlinger S (1997) Case report: cytomegalovirus infection as a cause of acute portal vein thrombosis. J Gastroenterol Hepatol 12:287–288PubMedCrossRefGoogle Scholar
  79. 79.
    Squizzato A, Gerdes VE, Buller HR (2005) Effects of human cytomegalovirus infection on the coagulation system. Thromb Haemost 93:403–410PubMedGoogle Scholar
  80. 80.
    Ofotokun I, Carlson C, Gitlin SD, Elta G, Singleton TP, Markovitz DM (2001) Acute cytomegalovirus infection complicated by vascular thrombosis: a case report. Clin Infect Dis 32:983–986PubMedCrossRefGoogle Scholar
  81. 81.
    Abgueguen P, Delbos V, Chennebault JM, Payan C, Pichard E (2003) Vascular thrombosis and acute cytomegalovirus infection in immunocompetent patients: report of 2 cases and literature review. Clin Infect Dis 36:E134–E139PubMedCrossRefGoogle Scholar
  82. 82.
    Khater FJ, Myers JW, Moorman JP (2003) A 45-year-old woman with fever and splenic infarcts. Clin Infect Dis 37:1125–1126CrossRefGoogle Scholar
  83. 83.
    Atzmony L, Halutz O, Avidor B, Finn T, Zimmerman O, Steinvil A, Zeltser D, Giladi M, Justo D (2010) Incidence of cytomegalovirus-associated thrombosis and its risk factors: a case-control study. Thromb Res 126:e439–e443PubMedCrossRefGoogle Scholar
  84. 84.
    Rovery C, Granel B, Parola P, Foucault C, Brouqui P (2005) Acute cytomegalovirus infection complicated by venous thrombosis: a case report. Ann Clin Microbiol Antimicrob 12:4–11Google Scholar
  85. 85.
    Delbos V, Abgueguen P, Chennebault JM, Fanello S, Pichard E (2007) Acute cytomegalovirus infection and venous thrombosis: role of antiphospholipid antibodies. J Infect 54:47–50CrossRefGoogle Scholar
  86. 86.
    Gharavi AE, Pierangeli SS, Espinola RG, Liu X, Colden-Stanfield M, Harris EN (2002) Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in vivo. 46:545–552Google Scholar
  87. 87.
    Benditt EP, Benditt JM (1973) Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci USA 70:1753–1756PubMedCrossRefGoogle Scholar
  88. 88.
    Gattone M, Iacoviello L, Colombo M, Castelnuovo AD, Soffiantino F, Gramoni A, Picco D, Benedetta M, Giannuzzi P (2001) Chlamydia pneumoniae and cytomegalovirus seropositivity, inflammatory markers, and the risk of myocardial infarction at a young age. Am Heart J 142:633–640PubMedCrossRefGoogle Scholar
  89. 89.
    Epstein SE, Zhou YF, Zhu J (1999) Infection and atherosclerosis: emerging mechanistic paradigms. Circulation 100:e20–e28PubMedGoogle Scholar
  90. 90.
    Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126PubMedCrossRefGoogle Scholar
  91. 91.
    Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143PubMedCrossRefGoogle Scholar
  92. 92.
    Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695PubMedCrossRefGoogle Scholar
  93. 93.
    Melnick JL, Petrie BL, Dreesman GR, McCollum CH, Petrie BL, Burek J, DeBakey ME (1983) Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet 2:644–647PubMedCrossRefGoogle Scholar
  94. 94.
    Hendrix MGR, Salimans MMM, van Boven CPA, Bruggeman CA (1990) High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol 136:23–28PubMedGoogle Scholar
  95. 95.
    Adam E, Melnick JL, Probtsfield JL, Petrie BL, Bailey KR, McCollum CH, DeBakey ME (1987) High level of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet 2:291–293PubMedCrossRefGoogle Scholar
  96. 96.
    Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE (1994) Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 256:391–394CrossRefGoogle Scholar
  97. 97.
    Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, Finkel T, Epstein SE (1996) Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335:624–630PubMedCrossRefGoogle Scholar
  98. 98.
    Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW, Szklo M (1996) Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation 94:922–927PubMedGoogle Scholar
  99. 99.
    Blum A, Giladi M, Weinberg M, Kaplan G, Pasternack H, Laniado S, Miller H (1998) High anti-cytomegalovirus (CMV) IgG antibody titer is associated with coronary artery disease and may predict post-coronary balloon angioplasty restenosis. Am J Cardiol 81:866–868PubMedCrossRefGoogle Scholar
  100. 100.
    Smith MG (1956) Propagation in tissues cultures of cytopathogenic virus from human salivary gland virus (SGV) disease. Proc Soc Exp Biol Med 92:424–430PubMedGoogle Scholar
  101. 101.
    Bale JF Jr, O’Neil ME (1989) Detection of murine cytomegalovirus DNA in circulating leukocytes harvested during acute infection of mice. J Virol 63:2667–2673PubMedGoogle Scholar
  102. 102.
    Fish KN, Depto AS, Moses AV, Britt W, Nelson JA (1995) Growth kinetics of human cytomegalovirus are altered in monocyte-derived macrophages. J Virol 69:3737–3743PubMedGoogle Scholar
  103. 103.
    Grefte A, Harmsen MC, van der Giessen M, Knollema S, van Son WJ, The TH (1994) Presence of human cytomegalovirus (HCMV) immediate early mRNA but not ppUL83 (lower matrix protein pp65) mRNA in polymorphonuclear and mononuclear leukocytes during active HCMV infection. J Gen Virol 75:1989–1998PubMedCrossRefGoogle Scholar
  104. 104.
    Hassan-Walker AF, Mattes FM, Griffiths PD, Emery VC (2001) Quantity of cytomegalovirus DNA in different leukocyte populations during active infection in vivo and the presence of gB and UL18 transcripts. J Med Virol 64:283–289PubMedCrossRefGoogle Scholar
  105. 105.
    Sinclair J, Sissons P (1996) Latent and persistent infections of monocytes and macrophages. Intervirology 39:293–301PubMedGoogle Scholar
  106. 106.
    Sinzger C, Jahn G (1996) Human cytomegalovirus cell tropism and pathogenesis. Intervirology 39:302–319PubMedGoogle Scholar
  107. 107.
    Gnann JW Jr, Ahlmén J, Svalander C, Olding L, Oldstone MB, Nelson JA (1988) Inflammatory cells in transplanted kidneys are infected by human cytomegalovirus. Am J Pathol 132:239–248PubMedGoogle Scholar
  108. 108.
    Manez R, Kusne S, Rinaldo C, Aguado JM, St George K, Grossi P, Frye B, Fung JJ, Ehrlich GD (1996) Time to detection of cytomegalovirus (CMV) DNA in blood leukocytes is a predictor for the development of CMV disease in CMV-seronegative recipients of allografts from CMV-seropositive donors following liver transplantation. J Infect Dis 173:1072–1076PubMedCrossRefGoogle Scholar
  109. 109.
    Plachter B, Sinzger C, Jahn G (1996) Cell types involved in replication and distribution of human cytomegalovirus. Adv Virus Res 46:195–261PubMedCrossRefGoogle Scholar
  110. 110.
    Saederup N, Lin YC, Dairaghi DJ, Schall TJ, Mocarski ES (1999) Cytomegalovirus-encoded beta chemokine promotes monocyte-associated viremia in the host. Proc Natl Acad Sci USA 96:10881–10886PubMedCrossRefGoogle Scholar
  111. 111.
    van der Strate BW, Hillebrands JL, Lycklama à Nijeholt SS, Beljaars L, Bruggeman CA, Van Luyn MJ, Rozing J, The TH, Meijer DK, Molema G, Harmsen MC (2003) Dissemination of rat cytomegalovirus through infected granulocytes and monocytes in vitro and in vivo. J Virol 77:11274–11278PubMedCrossRefGoogle Scholar
  112. 112.
    Gerna G, Zipeto D, Percivalle E, Parea M, Revello MG, Maccario R, Peri G, Milanesi G (1992) Human cytomegalovirus infection of the major leukocyte subpopulations and evidence for initial viral replication in polymorphonuclear leukocytes from viremic patients. J Infect Dis 166:1236–1244PubMedCrossRefGoogle Scholar
  113. 113.
    Taylor-Wiedeman J, Sissons P, Sinclair J (1994) Induction of endogenous human cytomegalovirus gene expression after differentiation of mono-cytes from healthy carriers. J Virol 68:1597–1604PubMedGoogle Scholar
  114. 114.
    Smith MS, Bentz GL, Alexander JS, Yurochko AD (2004) Human cytomegalovirus induces monocyte differentiation and migration as a strategy for dissemination and persistence. J Virol 78:4444–4453PubMedCrossRefGoogle Scholar
  115. 115.
    Smith MS, Bentz GL, Smith PM, Bivins ER, Yurochko AD (2004) HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner. J Leukoc Biol 76:65–76PubMedCrossRefGoogle Scholar
  116. 116.
    Isaacson MK, Juckem LK, Compton T (2008) Virus entry and innate immune activation. Curr Top Microbiol Immunol 325:85–100PubMedCrossRefGoogle Scholar
  117. 117.
    Soroceanu L, Akhavan A, Cobbs CS (2008) Platelet derived growth factor-alpha receptor activation is required for human cytomegalovirus infection. Nature 455:391–395PubMedCrossRefGoogle Scholar
  118. 118.
    Eggers M, Radsak K, Enders G, Reschke M (2001) Use of recombinant antigens gB and gH for diagnosis of primary human cytomegalovirus infection during pregnancy. J Med Virol 63:135–142PubMedCrossRefGoogle Scholar
  119. 119.
    Pass RF (2009) Development and evidence for efficacy of CMV glycoprotein B vaccine with MF59 adjuvant. J Clin Virol 46(Suppl 4):S73–S76PubMedCrossRefGoogle Scholar
  120. 120.
    Cui X, Meza BP, Adler SP, McVoy MA (2008) Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine 26:5760–5766PubMedCrossRefGoogle Scholar
  121. 121.
    Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, Sarasini A, Wagner M, Gallina A, Milanesi G, Koszinowski U, Baldanti F, Gerna G (2004) Human cytomegalovirus UL131–128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78:10023–10033PubMedCrossRefGoogle Scholar
  122. 122.
    Saccoccio FM, Sauer AL, Cui X, Armstrong AE, Habib el-SE, Johnson DC, Ryckman BJ, Klingelhutz AJ, Adler SP, McVoy MA (2011) Peptides from cytomegalovirus UL130 and UL131 proteins induce high titer antibodies that block viral entry into mucosal epithelial cells. Vaccine 29:2705–2711PubMedCrossRefGoogle Scholar
  123. 123.
    Gerna G, Sarasini A, Patrone M, Percivalle E, Fiorina L, Campanini G, Gallina A, Baldanti F, Revello MG (2008) Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection. J Gen Virol 89:853–865PubMedCrossRefGoogle Scholar
  124. 124.
    Macagno A, Bernasconi NL, Vanzetta F, Dander E, Sarasini A, Revello MG, Gerna G, Sallusto F, Lanzavecchia A (2010) Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128–131A complex. J Virol 84:1005–1013PubMedCrossRefGoogle Scholar
  125. 125.
    Oliver SE, Cloud GA, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, Vaudry W, Pass RF, Soong SJ, Whitley RJ, Kimberlin DW (2009) Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system; National Institute of Allergy, Infectious Diseases Collaborative Antiviral Study Group. J Clin Virol 46(Suppl 4):S22–S26PubMedCrossRefGoogle Scholar
  126. 126.
    Jabs DA (2001) The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: the ganciclovir cidofovir cytomegalovirus retinitis trial. Am J Ophthalmol 131:457–467CrossRefGoogle Scholar
  127. 127.
    Jabs DA, Van Natta ML, Holbrook JT, Kempen JH, Meinert CL, Davis MD (2007) Longitudinal study of the ocular complications of AIDS:1. Ocular diagnoses at enrollment. Ophthalmology 114:780–786PubMedCrossRefGoogle Scholar
  128. 128.
    Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, Robinson CA, Stempien MJ (2002) A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 347:1119–1126CrossRefGoogle Scholar
  129. 129.
    Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD (2004) Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients; Valganciclovir Solid Organ Transplant Study Group. Am J Transplant 4:611–620PubMedCrossRefGoogle Scholar
  130. 130.
    Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, Finke J, Cordonnier C, Link H, Ljungman P (2002) Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation; Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 99:1159–1164PubMedCrossRefGoogle Scholar
  131. 131.
    Boeckh M, Geballe AP (2011) Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 121:1673–1680PubMedCrossRefGoogle Scholar
  132. 132.
    Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, Norman D, Mendez R, Keating MR, Coggon GL, Crisp A, Lee IC (1990) Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation; International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med 340:1462–1470CrossRefGoogle Scholar
  133. 133.
    Blumberg EA, Hauser IA, Stanisic S, Mueller E, Berenson K, Gahlemann CG, Humar A, Jardine AG (2010) Prolonged prophylaxis with valganciclovir is cost effective in reducing posttransplant cytomegalovirus disease within the United States. Transplantation 90:1420–1426PubMedCrossRefGoogle Scholar
  134. 134.
    Riba Solé M, Farré Riba R, Badell Serra I, Mangues Bafalluy MA (2011) Acyclovir-induced acute renal failure in a paediatric oncology patient. Farm Hosp 35(5):281–282PubMedCrossRefGoogle Scholar
  135. 135.
    Lurain NS, Chou S (2010) Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 23:689–712PubMedCrossRefGoogle Scholar
  136. 136.
    Bidanset DJ, Beadle JR, Wan WB, Hostetler KY, Kern ER (2004) Oral activity of ether lipid ester prodrugs of cidofovir against experimental human cytomegalovirus infection. J Infect Dis 190:499–503PubMedCrossRefGoogle Scholar
  137. 137.
    Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, Ruebsamen-Schaeff H, Zimmermann H (2010) In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother 54:1290–1297PubMedCrossRefGoogle Scholar
  138. 138.
    Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, Alangaden GJ, Chemaly RF, Petersen F, Chao N, Klein J, Sprague K, Villano SA, Boeckh M (2008) Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, doseranging study. Blood 111:5403–5410PubMedCrossRefGoogle Scholar
  139. 139.
    Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, Young JA, Rodriguez T, Maertens J, Schmitt M, Einsele H, Ferrant A, Lipton JH, Villano SA, Chen H, Boeckh M (2011) Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial; Maribavir 1263-300 Clinical Study Group. Lancet Infect Dis 11:284–292PubMedCrossRefGoogle Scholar
  140. 140.
    Avery RK, Mossad SB, Poggio E, Lard M, Budev M, Bolwell B, Waldman WJ, Braun W, Mawhorter SD, Fatica R, Krishnamurthi V, Young JB, Shrestha R, Stephany B, Lurain N, Yen-Lieberman B (2010) Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation 90:419–426PubMedCrossRefGoogle Scholar
  141. 141.
    Hodson EM, Jones CA, Strippoli GF, Webster AC, Craig JC (2007) Immunoglobulins, vaccines or interferon for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2:CD005129PubMedGoogle Scholar
  142. 142.
    Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O (2009) Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol 27:770–781PubMedCrossRefGoogle Scholar
  143. 143.
    Nigro G, Adler SP, La Torre R, Best AM (2005) Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353:1350–1362PubMedCrossRefGoogle Scholar
  144. 144.
    Bate SL, Dollard SC, Cannon MJ (2010) Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988–2004. J Infect Dis 50:1439–1447CrossRefGoogle Scholar
  145. 145.
    Nichols WG, Price TH, Gooley T, Corey L, Boeckh M (2003) Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood 101:4195–4200PubMedCrossRefGoogle Scholar
  146. 146.
    Cunha BA (2010) Cytomegalovirus pneumonia: community-acquired pneumonia in immunocompetent hosts. Infect Dis Clin North Am 24:147–158PubMedCrossRefGoogle Scholar
  147. 147.
    Matsumura T, Narimatsu H, Kami M, Yuji K, Kusumi E, Hori A, Murashige N, Tanaka Y, Masuoka K, Wake A, Miyakoshi S, Kanda Y, Taniguchi S (2007) Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients. Biol Blood Marrow Transplant 13:577–583PubMedCrossRefGoogle Scholar
  148. 148.
    Ljungman P, Hakki M, Boeckh M (2010) Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect Dis Clin North Am 24:319–337PubMedCrossRefGoogle Scholar
  149. 149.
    Pollack M, Heugel J, Xie H, Leisenring W, Storek J, Young JA, Kukreja M, Gress R, Tomblyn M, Boeckh M (2011) An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 17:664–673PubMedCrossRefGoogle Scholar
  150. 150.
    Fishman JA, Rubin RH (1998) Infection in organ-transplant recipients. N Engl J Med 338:1741–1751PubMedCrossRefGoogle Scholar
  151. 151.
    La Rosa C, Limaye AP, Krishnan A, Blumstein G, Longmate J, Diamond DJ (2011) Primary response against cytomegalovirus during antiviral prophylaxis with valganciclovir, in solid organ transplant recipients. Transpl Int. doi:10.1111/j.1432-2277.2011.01285.x
  152. 152.
    Guitard J, Rostaing L, Kamar N (2011) New-onset diabetes and nephropathy after renal transplantation. Contrib Nephrol 170:247–255PubMedCrossRefGoogle Scholar
  153. 153.
    Maglione M, Biebl MO, Bonatti H, Göbel G, Ratschiller T, Schneeberger S, Brandacher G, Hengster P, Margreiter C, Berger N, Margreiter R, Pratschke J, Mark W (2010) Cytomegalovirus mismatch as major risk factor for delayed graft function after pancreas transplantation. Transplantation 90:666–671PubMedCrossRefGoogle Scholar
  154. 154.
    Shlobin OA, West EE, Lechtzin N, Miller SM, Borja M, Orens JB, Dropulic LK, McDyer JF (2006) Persistent cytomegalovirus-specific memory responses in the lung allograft and blood following primary infection in lung transplant recipients. J Immunol 176:2625–2634PubMedGoogle Scholar
  155. 155.
    Christie JD, Edwards LB, Aurora P, Dobbels F, Kirk R, Rahmel AO, Taylor DO, Kucheryavaya AY, Hertz MI (2008) Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult lung and heart/lung transplantation report-2008. J Heart Lung Transplant 27:957–969PubMedCrossRefGoogle Scholar
  156. 156.
    Sester U, Gärtner BC, Wilkens H, Schwaab B, Wössner R, Kindermann I, Girndt M, Meyerhans A, Mueller-Lantzsch N, Schäfers HJ, Sybrecht GW, Köhler H, Sester M (2005) Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant 5:1483–1489PubMedCrossRefGoogle Scholar
  157. 157.
    Costa C, Astegiano S, Terlizzi ME, Sidoti F, Curtoni A, Solidoro P, Baldi S, Bergallo M, Cavallo R (2011) Evaluation and significance of cytomegalovirus-specific cellular immune response in lung transplant recipients. Transplant Proc 43:1159–1161PubMedCrossRefGoogle Scholar
  158. 158.
    Kwakkel-van Erp JM, Paantjens AW, van Kessel DA, Grutters JC, van den Bosch JM, van de Graaf EA, Otten HG (2011) Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation. Clin Exp Immunol. doi:10.1111/j.1365-2249.2011.04436.x
  159. 159.
    da Cunha-Bang C, Sørensen SS, Iversen M, Sengeløv H, Hillingsø JG, Rasmussen A, Mortensen SA, Fox ZV, Kirkby NS, Christiansen CB, Lundgren JD (2011) Factors associated with the development of cytomegalovirus infection following solid organ transplantation. Scand J Infect Dis 43:360–365PubMedCrossRefGoogle Scholar
  160. 160.
    Lefeuvre S, Chevalier P, Charpentier C, Zekkour R, Havard L, Benammar M, Amrein C, Boussaud V, Lillo-Le Louët A, Guillemain R, Billaud EM (2010) Valganciclovir prophylaxis for cytomegalovirus infection in thoracic transplant patients: retrospective study of efficacy, safety, and drug exposure. Transpl Infect Dis 12:213–219PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Milan Popović
    • 1
  • Katarina Smiljanić
    • 1
  • Branislava Dobutović
    • 1
  • Tatiana Syrovets
    • 2
  • Thomas Simmet
    • 2
  • Esma R. Isenović
    • 1
  1. 1.Department for Radiobiology and Molecular Genetics, Vinča InstituteUniversity of BelgradeBelgradeSerbia
  2. 2.Institute of Pharmacology of Natural Products & Clinical PharmacologyUlm UniversityUlmGermany

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