, Volume 10, Issue 2, pp 251–265 | Cite as

Cell death suppression by cytomegaloviruses



Cytomegaloviruses (CMVs), a subset of betaherpesviruses, employ multiple strategies to suppress apoptosis in infected cells and thus to delay their death. Human cytomegalovirus (HCMV) encodes at least two proteins that directly interfere with the apoptotic signaling pathways, viral inhibitor of caspase-8-induced apoptosis vICA (pUL36), and mitochondria-localized inhibitor of apoptosis vMIA (pUL37 × 1). vICA associates with pro-caspase-8 and appears to block its recruitment to the death-inducing signaling complex (DISC), a step preceding caspase-8 activation. vMIA binds and sequesters Bax at mitochondria, and interferes with BH3-only-death-factor/Bax-complex-mediated permeabilization of mitochondria. vMIA does not seem to either interact with Bak, a close structural and functional homologue of Bax, or to suppress Bak-mediated permeabilization of mitochondria and Bak-mediated apoptosis. All sequenced betaherpesviruses, including CMVs, encode close homologues of vICA, and those vICA homologues that have been tested, were found to be functional cell death suppressors. Overt sequence homologues of vMIA were found only in the genomes of primate CMVs, but recent observations made with murine CMV (MCMV) indicate that non-primate CMVs may also encode a cell death suppressor functionally resembling vMIA. The exact physiological rolesand relative contributions of vMIA and vICA in suppressing death of CMV-infected cells in vivo have not been elucidated. There is strong evidence that the cell death suppressing function of vMIA is indispensable, and that vICA is dispensable for replication of HCMV. In addition to suppressed caspase-8 activation and sequestered Bax, CMV-infected cells display several other phenomena, less well characterized, that may diminish, directly or indirectly the extent of cell death.


alphaherpesvirus apoptosis Bak Bax Bcl-2 betaherpesvirus caspase-8 cell death suppressor cytomegalovirus gammaherpesvirus herpesvirus inhibitor of apoptosis programmed cell death vICA vMIA 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    O’Brien V. Viruses and apoptosis. J Gen Virol 1998; 79(Pt 8): 1833–1845.PubMedGoogle Scholar
  2. 2.
    Tschopp J, Thome M, Hofmann K, et al. The fight of viruses against apoptosis. Curr Opin Genet Dev 1998; 8: 82–87.PubMedGoogle Scholar
  3. 3.
    Wallach D, Varfolomeev EE, Malinin NL, et al. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 1999; 17: 331–367.PubMedGoogle Scholar
  4. 4.
    Smyth MJ, Kelly JM, Sutton VR, et al. Unlocking the secrets of cytotoxic granule proteins. J Leukoc Biol 2001; 70: 18–29.PubMedGoogle Scholar
  5. 5.
    Goldmacher VS. vMIA, a viral inhibitor of apoptosis targeting mitochondria. Biochimie 2002; 84: 177–185.PubMedGoogle Scholar
  6. 6.
    Castillo JP, Kowalik TF. HCMV infection: Modulating the cell cycle and cell death. Int Rev Immunol 2004; 23: 113–139.PubMedGoogle Scholar
  7. 7.
    Lagunoff M, Carroll PA. Inhibition of apoptosis by the gamma-herpesviruses. Int Rev Immunol 2003; 22: 373–399.PubMedGoogle Scholar
  8. 8.
    Boya P, Roumier T, Andreau K, et al. Mitochondrion-targeted apoptosis regulators of viral origin. Biochem Biophys Res Commun 2003; 304: 575–581.PubMedGoogle Scholar
  9. 9.
    Cuconati A, White E. Viral homologs of BCL-2: Role of apoptosis in the regulation of virus infection. Genes Dev 2002; 16: 2465–2478.PubMedGoogle Scholar
  10. 10.
    Derfuss T, Meinl E. Herpesviral proteins regulating apoptosis. Curr Top Microbiol Immunol 2002; 269: 257–272.PubMedGoogle Scholar
  11. 11.
    Polster BM, Pevsner J, Hardwick JM. Viral Bcl-2 homologs and their role in virus replication and associated diseases. Biochim Biophys Acta 2004; 1644: 211–227.CrossRefPubMedGoogle Scholar
  12. 12.
    Benedict CA, Norris PS, Ware CF. To kill or be killed: Viral evasion of apoptosis. Nat Immunol 2002; 3: 1013–1018.CrossRefPubMedGoogle Scholar
  13. 13.
    Goodkin ML, Morton ER, Blaho JA. Herpes simplex virus infection and apoptosis. Int Rev Immunol 2004; 23: 141–172.PubMedGoogle Scholar
  14. 14.
    Michaelis M, Kotchetkov R, Vogel JU, et al. Cytomegalovirus infection blocks apoptosis in cancer cells. Cell Mol Life Sci 2004; 61: 1307–1316.PubMedGoogle Scholar
  15. 15.
    Goldmacher VS. Cell death suppressors encoded by cytomegalovirus. Prog Mol Subcell Biol 2004; 36: 1–18.PubMedGoogle Scholar
  16. 16.
    Skaletskaya A, Bartle LM, Chittenden T, et al. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc Natl Acad Sci USA 2001; 98: 7829–7834.PubMedGoogle Scholar
  17. 17.
    Krueger A, Baumann S, Krammer PH, et al. FLICE-inhibitory proteins: Regulators of death receptor-mediated apoptosis. Mol Cell Biol 2001; 21: 8247–8254.CrossRefPubMedGoogle Scholar
  18. 18.
    McCormick AL, Skaletskaya A, Barry PA, et al. Differential function and expression of the viral inhibitor of caspase 8-induced apoptosis (vICA) and the viral mitochondria-localized inhibitor of apoptosis (vMIA) cell death suppressors conserved in primate and rodent cytomegaloviruses. Virology 2003; 316: 221–233.PubMedGoogle Scholar
  19. 19.
    Menard C, Wagner M, Ruzsics Z, et al. Role of murine cytomegalovirus US22 gene family members in replication in macrophages. J Virol 2003; 77: 5557–5570.PubMedGoogle Scholar
  20. 20.
    Hansen SG, Strelow LI, Franchi DC, et al. Complete sequence and genomic analysis of rhesus cytomegalovirus. J Virol 2003; 77: 6620–6636.PubMedGoogle Scholar
  21. 21.
    Liu Y, Biegalke BJ. Characterization of a cluster of late genes of guinea pig cytomegalovirus. Virus Genes 2001; 23: 247&256PubMedGoogle Scholar
  22. 22.
    Thome M, Schneider P, Hofmann K, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997; 386: 517–521.PubMedGoogle Scholar
  23. 23.
    Wang GH, Bertin J, Wang Y, et al. Bovine herpesvirus 4 BORFE2 protein inhibits Fas- and tumor necrosis factor receptor 1-induced apoptosis and contains death effector domains shared with other gamma-2 herpesviruses. J Virol 1997; 71: 8928–8932.PubMedGoogle Scholar
  24. 24.
    Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388: 190–195.PubMedGoogle Scholar
  25. 25.
    Scaffidi C, Schmitz I, Krammer PH, et al. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 1999; 274: 1541–1548.PubMedGoogle Scholar
  26. 25a.
    Guasparri I, Keller SA, Cesarman E. KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 2004; 199: 993–1003.PubMedGoogle Scholar
  27. 26.
    Chen P, Tian J, Kovesdi I, et al. Interaction of the adenovirus 14.7-kDa protein with FLICE inhibits Fas ligand-induced apoptosis. J Biol Chem 1998; 273: 5815–5820.PubMedGoogle Scholar
  28. 27.
    Scaffidi C, Schmitz I, Zha J, et al. Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 1999; 274: 22532–22538.PubMedGoogle Scholar
  29. 28.
    Engels IH, Stepczynska A, Stroh C, et al. Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 2000; 19: 4563–4573.PubMedGoogle Scholar
  30. 29.
    Goldmacher VS, Bartle LM, Skaletskaya A, et al. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sci USA 1999; 96: 12536–12541.PubMedGoogle Scholar
  31. 30.
    Su Y, Testaverde JR, Davis CN, et al. Human cytomegalovirus UL37 immediate early target minigene RNAs are accurately spliced and polyadenylated. J Gen Virol 2003; 84: 29–39.PubMedGoogle Scholar
  32. 31.
    Adair R, Liebisch GW, Colberg-Poley AM. Complex alternative processing of human cytomegalovirus UL37 pre-mRNA. J Gen Virol 2003; 84: 3353–3358.PubMedGoogle Scholar
  33. 32.
    Roumier T, Vieira HL, Castedo M, et al. The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway. Cell Death Differ 2002; 9: 1212–1219.PubMedGoogle Scholar
  34. 33.
    Boya P, Cohen I, Zamzami N, et al. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ 2002; 9: 465–467.PubMedGoogle Scholar
  35. 34.
    Poncet D, Larochette N, Pauleau AL, et al. An anti-apoptotic viral protein that recruits Bax to mitochondria. J Biol Chem 2004; 279: 22605–22614.PubMedGoogle Scholar
  36. 35.
    Mavinakere MS, Colberg-Poley AM. Dual targeting of the human cytomegalovirus UL37 exon 1 protein during permissive infection. J Gen Virol 2004; 85: 323–329.PubMedGoogle Scholar
  37. 36.
    Colberg-Poley AM, Patel MB, Erezo DP, et al. Human cytomegalovirus UL37 immediate-early regulatory proteins traffic through the secretory apparatus and to mitochondria. J Gen Virol 2000; 81: 1779–1789.PubMedGoogle Scholar
  38. 37.
    Al-Barazi HO, Colberg-Poley AM. The human cytomegalovirus UL37 immediate-early regulatory protein is an integral membrane N-glycoprotein which traffics through the endoplasmic reticulum and Golgi apparatus. J Virol 1996; 70: 7198–7208.PubMedGoogle Scholar
  39. 38.
    Brune W, Nevels M, Shenk T. Murine cytomegalovirus m41 open reading frame encodes a Golgi-localized antiapoptotic protein. J Virol 2003; 77: 11633–11643.PubMedGoogle Scholar
  40. 39.
    Kouzarides T, Bankier AT, Satchwell SC, et al. An immediate early gene of human cytomegalovirus encodes a potential membrane glycoprotein. Virology 1988; 165: 151–164.PubMedGoogle Scholar
  41. 40.
    Mavinakere MS, Colberg-Poley AM. Internal cleavage of the human cytomegalovirus UL37 immediate-early glycoprotein and divergent trafficking of its proteolytic fragments. J Gen virol 2004; 85: 1989–1994.PubMedGoogle Scholar
  42. 41.
    Hayajneh WA, Colberg-Poley AM, Skaletskaya A, et al. The sequence and antiapoptotic functional domains of the human cytomegalovirus UL37 exon 1 immediate early protein are conserved in multiple primary strains. Virology 2001; 279: 233–240.PubMedGoogle Scholar
  43. 42.
    Arnoult D, Bartle LM, Skaletskaya A, et al. Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria. Proc Natl Acad Sci USA 2004; 101: 7988–7993.PubMedGoogle Scholar
  44. 43.
    Shimizu S, Narita M, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 1999; 399: 483–487.PubMedGoogle Scholar
  45. 44.
    Belzacq AS, Vieira HL, Kroemer G, et al. The adenine nucleotide translocator in apoptosis. Biochimie 2002; 84: 167–176.PubMedGoogle Scholar
  46. 45.
    Vieira HL, Belzacq AS, Haouzi D, et al. The adenine nucleotide translocator: A target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene 2001; 20: 4305–4316.PubMedGoogle Scholar
  47. 46.
    Vieira HL, Boya P, Cohen I, et al. Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-X(L). Oncogene 2002; 21: 1963–1977.PubMedGoogle Scholar
  48. 47.
    Letai A, Bassik MC, Walensky LD, et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2: 183–192.PubMedGoogle Scholar
  49. 48.
    Zong WX, Li C, Hatzivassiliou G, et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 2003; 162: 59–69.PubMedGoogle Scholar
  50. 49.
    Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: A control point for apoptosis. Science 2003; 300: 135–139.CrossRefPubMedGoogle Scholar
  51. 50.
    Karbowski M, Lee YJ, Gaume B, et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 2002; 159: 931–938.PubMedGoogle Scholar
  52. 51.
    McCormick AL, Smith VL, Chow D, et al. Disruption of mitochondrial networks by the human cytomegalovirus UL37 gene product viral mitochondrion-localized inhibitor of apoptosis. J Virol 2003; 77: 631–641.PubMedGoogle Scholar
  53. 52.
    Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. Embo J 1998; 17: 1675–1687.PubMedGoogle Scholar
  54. 53.
    Foghsgaard L, Jaattela M. The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type. J Virol 1997; 71: 7509–7517.PubMedGoogle Scholar
  55. 54.
    Belka C, Rudner J, Wesselborg S, et al. Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis. Oncogene 2000; 19: 1181–1190.PubMedGoogle Scholar
  56. 55.
    Newton K, Strasser A. Ionizing radiation and chemotherapeutic drugs induce apoptosis in lymphocytes in the absence of Fas or FADD/MORT1 signaling. Implications for cancer therapy. J Exp Med 2000; 191: 195–200.PubMedGoogle Scholar
  57. 56.
    Yu J, Zhang L, Hwang PM, et al. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 2001; 7: 673&682.PubMedGoogle Scholar
  58. 57.
    Han J, Flemington C, Houghton AB, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA 2001; 98: 11318–23.PubMedGoogle Scholar
  59. 58.
    Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288: 1053–1058.PubMedGoogle Scholar
  60. 59.
    Boya P, Gonzalez-Polo RA, Poncet D, et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003; 22: 3927–3936.PubMedGoogle Scholar
  61. 60.
    Strasser A, Harris AW, Huang DC, et al. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. Embo J 1995; 14: 6136–6147.PubMedGoogle Scholar
  62. 61.
    Cartron PF, Juin P, Oliver L, et al. Nonredundant role of Bax and Bak in Bid-mediated apoptosis. Mol Cell Biol 2003; 23: 4701–4712.PubMedGoogle Scholar
  63. 62.
    Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 2001; 292: 727–730.CrossRefPubMedGoogle Scholar
  64. 63.
    Wei MC, Lindsten T, Mootha VK, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14: 2060–2071.PubMedGoogle Scholar
  65. 64.
    Andoniou CE, Andrews DM, Manzur M, et al. A novel checkpoint in the Bcl-2-regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells. J Cell Biol 2004; 166: 827–837.PubMedGoogle Scholar
  66. 65.
    Borst EM, Hahn G, Koszinowski UH, et al. Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: A new approach for construction of HCMV mutants. J Virol 1999; 73: 8320–8329.PubMedGoogle Scholar
  67. 66.
    Dunn W, Chou C, Li H, et al. Functional profiling of a human cytomegalovirus genome. Proc Natl Acad Sci USA 2003; 100: 14223–14228.PubMedGoogle Scholar
  68. 67.
    Yu D, Silva MC, Shenk T. Functional map of human cytomegalovirus AD169 defined by global mutational analysis. Proc Natl Acad Sci USA 2003; 100: 12396–12401.PubMedGoogle Scholar
  69. 68.
    Lee M, Xiao J, Haghjoo E, et al. Murine cytomegalovirus containing a mutation at open reading frame M37 is severely attenuated in growth and virulence in vivo. J Virol 2000; 74: 11099–11107.PubMedGoogle Scholar
  70. 69.
    Colberg-Poley AM, Huang L, Soltero VE, et al. The acidic domain of pUL37x1 and gpUL37 plays a key role in transactivation of HCMV DNA replication gene promoter constructions. Virology 1998; 246: 400–408.PubMedGoogle Scholar
  71. 70.
    Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8: 705–711.PubMedGoogle Scholar
  72. 71.
    Hsu YT, Youle RJ. Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem 1997; 272: 13829–13834.PubMedGoogle Scholar
  73. 72.
    Mikhailov V, Mikhailova M, Pulkrabek DJ, et al. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J Biol Chem 2001; 276: 18361–18374.PubMedGoogle Scholar
  74. 73.
    Cheng EH, Nicholas J, Bellows DS, et al. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci USA 1997; 94: 690–694.PubMedGoogle Scholar
  75. 74.
    Holmgreen SP, Huang DC, Adams JM, et al. Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members. Cell Death Differ 1999; 6: 525–532.PubMedGoogle Scholar
  76. 75.
    Simonian PL, Grillot DA, Merino R, et al. Bax can antagonize Bcl-XL during etoposide and cisplatin-induced cell death independently of its heterodimerization with Bcl-XL. J Biol Chem 1996; 271: 22764–22772.PubMedGoogle Scholar
  77. 76.
    Simonian PL, Grillot DA, Nunez G. Bak can accelerate chemotherapy-induced cell death independently of its heterodimerization with Bcl-XL and Bcl-2. Oncogene 1997; 15: 1871–1875.PubMedGoogle Scholar
  78. 77.
    Cheng EH, Levine B, Boise LH, et al. Bax-independent inhibition of apoptosis by Bcl-XL. Nature 1996; 379: 554–556.PubMedGoogle Scholar
  79. 78.
    Zha H, Reed JC. Heterodimerization-independent functions of cell death regulatory proteins Bax and Bcl-2 in yeast and mammalian cells. J Biol Chem 1997; 272: 31482–31488.PubMedGoogle Scholar
  80. 79.
    Wolter KG, Hsu YT, Smith CL, et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 1997; 139: 1281–1292.CrossRefPubMedGoogle Scholar
  81. 80.
    Desagher S, Osen-Sand A, Nichols A, et al. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 1999; 144: 891–901.PubMedGoogle Scholar
  82. 81.
    Guo B, Zhai D, Cabezas E, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 2003; 423: 456–461.PubMedGoogle Scholar
  83. 82.
    Sawada M, Sun W, Hayes P, et al. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 2003; 5: 320–329.PubMedGoogle Scholar
  84. 83.
    Samuel T, Weber HO, Rauch P, et al. The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax. J Biol Chem 2001; 276: 45201–45206.PubMedGoogle Scholar
  85. 84.
    Nomura M, Shimizu S, Sugiyama T, et al. 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax. J Biol Chem 2003; 278: 2058–2065.CrossRefPubMedGoogle Scholar
  86. 85.
    Sundararajan R, White E. E1B 19K blocks Bax oligomerization and tumor necrosis factor alpha-mediated apoptosis. J Virol 2001; 75: 7506–7516.PubMedGoogle Scholar
  87. 86.
    Chung YL, Sheu ML, Yen SH. Hepatitis C virus NS5A as a potential viral Bcl-2 homologue interacts with Bax and inhibits apoptosis in hepatocellular carcinoma. Int J Cancer 2003; 107: 65–73.PubMedGoogle Scholar
  88. 87.
    Massari P, King CA, Ho AY, et al. Neisserial PorB is translocated to the mitochondria of HeLa cells infected with Neisseria meningitidis and protects cells from apoptosis. Cell Microbiol 2003; 5: 99–109.PubMedGoogle Scholar
  89. 88.
    Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996; 274: 782–784.CrossRefPubMedGoogle Scholar
  90. 89.
    Liu ZG, Hsu H, Goeddel DV, et al. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 1996; 87: 565–576.PubMedGoogle Scholar
  91. 90.
    Van Antwerp DJ, Martin SJ, Kafri T, et al. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 1996; 274: 787–789.PubMedGoogle Scholar
  92. 91.
    Wang CY, Mayo MW, Baldwin AS, Jr. TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-kappaB. Science 1996; 274: 784–787.CrossRefPubMedGoogle Scholar
  93. 92.
    Goodkin ML, Ting AT, Blaho JA. NF-kappaB Is Required for Apoptosis Prevention during Herpes Simplex Virus Type 1 Infection. J Virol 2003; 77: 7261–7280.PubMedGoogle Scholar
  94. 93.
    Yurochko AD, Kowalik TF, Huong SM, et al. Human cytomegalovirus upregulates NF-kappa B activity by transactivating the NF-kappa B p105/p50 and p65 promoters. J Virol 1995; 69: 5391–5400.PubMedGoogle Scholar
  95. 94.
    Gribaudo G, Ravaglia S, Guandalini L, et al. The murine cytomegalovirus immediate-early 1 protein stimulates NF-kappa B activity by transactivating the NF-kappa B p105/p50 promoter. Virus Res 1996; 45: 15–27.PubMedGoogle Scholar
  96. 95.
    Benedict CA, Angulo A, Patterson G, et al. Neutrality of the canonical NF-kappaB-dependent pathway for human and murine cytomegalovirus transcription and replication in vitro. J Virol 2004; 78: 741–750.PubMedGoogle Scholar
  97. 96.
    Campbell KJ, Rocha S, Perkins ND. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 2004; 13: 853–865.PubMedGoogle Scholar
  98. 97.
    Zhu H, Shen Y, Shenk T. Human cytomegalovirus IE1 and IE2 proteins block apoptosis. J Virol 1995; 69: 7960&7970.PubMedGoogle Scholar
  99. 98.
    Baillie J, Sahlender DA, Sinclair JH. Human Cytomegalovirus Infection Inhibits Tumor Necrosis Factor Alpha (TNF-alpha) Signaling by Targeting the 55-Kilodalton TNF-alpha Receptor. J Virol 2003; 77: 7007–7016.PubMedGoogle Scholar
  100. 99.
    Tanaka K, Zou JP, Takeda K, et al. Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells. Circulation 1999; 99: 1656–1659.PubMedGoogle Scholar
  101. 100.
    Kim J, Kwon YJ, Park ES, et al. Human cytomegalovirus (HCMV) IE1 plays role in resistance to apoptosis with etoposide in cancer cell line by Cdk2 accumulation. Microbiol Immunol 2003; 47: 959–967.PubMedGoogle Scholar
  102. 101.
    Speir E, Modali R, Huang ES, et al. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 1994; 265: 391–394.PubMedGoogle Scholar
  103. 102.
    Muganda P, Mendoza O, Hernandez J, et al. Human cytomegalovirus elevates levels of the cellular protein p53 in infected fibroblasts. J Virol 1994; 68: 8028–8034.PubMedGoogle Scholar
  104. 103.
    Deng Y, Wu X. Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria. Proc Natl Acad Sci USA 2000; 97: 12050–12055.PubMedGoogle Scholar
  105. 104.
    Erster S, Mihara M, Kim RH, et al. In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol Cell Biol 2004; 24: 6728–6741.CrossRefPubMedGoogle Scholar
  106. 105.
    Kovacs A, Weber ML, Burns LJ, et al. Cytoplasmic sequestration of p53 in cytomegalovirus-infected human endothelial cells. Am J Pathol 1996; 149: 1531–1539.PubMedGoogle Scholar
  107. 106.
    Wang J, Belcher JD, Marker PH, et al. Cytomegalovirus inhibits p53 nuclear localization signal function. J Mol Med 2001; 78: 642–647.PubMedGoogle Scholar
  108. 107.
    Tsai HL, Kou GH, Chen SC, et al. Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. J Biol Chem 1996; 271: 3534–3540.PubMedGoogle Scholar
  109. 108.
    Wang J, Marker PH, Belcher JD, et al. Human cytomegalovirus immediate early proteins upregulate endothelial p53 function. FEBS Lett 2000; 474: 213–216.CrossRefPubMedGoogle Scholar
  110. 109.
    Fortunato EA, Spector DH. p53 and RPA are sequestered in viral replication centers in the nuclei of cells infected with human cytomegalovirus. J Virol 1998; 72: 2033–2039.PubMedGoogle Scholar
  111. 110.
    Allart S, Martin H, Detraves C, et al. Human cytomegalovirus induces drug resistance and alteration of programmed cell death by accumulation of deltaN-p73alpha. J Biol Chem 2002; 277: 29063–29068.PubMedGoogle Scholar
  112. 111.
    Brune W, Menard C, Heesemann J, et al. A ribonucleotide reductase homolog of cytomegalovirus and endothelial cell tropism. Science 2001; 291: 303–305.PubMedGoogle Scholar
  113. 112.
    Lembo D, Donalisio M, Hofer A, et al. The ribonucleotide reductase R1 homolog of murine cytomegalovirus is not a functional enzyme subunit but is required for pathogenesis. J Virol 2004; 78: 4278–4288.PubMedGoogle Scholar
  114. 113.
    Langelier Y, Bergeron S, Chabaud S, et al. The R1 subunit of herpes simplex virus ribonucleotide reductase protects cells against apoptosis at, or upstream of, caspase-8 activation. J Gen Virol 2002; 83: 2779–2789.PubMedGoogle Scholar
  115. 114.
    Hahn G, Khan H, Baldanti F, et al. The Human Cytomegalovirus Ribonucleotide Reductase Homolog UL45 Is Dispensable for Growth in Endothelial Cells, as Determined by a BAC-Cloned Clinical Isolate of Human Cytomegalovirus with Preserved Wild-Type Characteristics. J Virol 2002; 76: 9551–9555.PubMedGoogle Scholar
  116. 115.
    Patrone M, Percivalle E, Secchi M, et al. The human cytomegalovirus UL45 gene product is a late, virion-associated protein and influences virus growth at low multiplicities of infection. J Gen Virol 2003; 84: 3359–3370.PubMedGoogle Scholar
  117. 116.
    Billstrom Schroeder M, Christensen R, Worthen GS. Human cytomegalovirus protects endothelial cells from apoptosis induced by growth factor withdrawal. J Clin Virol 2002; 25(Suppl 2): S149&S157.PubMedGoogle Scholar
  118. 117.
    Harkins L, Volk AL, Samanta M, et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet 2002; 360: 1557–1563.PubMedGoogle Scholar
  119. 118.
    Cinatl J, Jr., Cinatl J, Vogel JU, et al. Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. Cancer Res 1998; 58: 367–372.PubMedGoogle Scholar
  120. 119.
    Hahn G, Eichhorst ST, Korn B, et al. An anti-apoptotic protein of human cytomegalovirus enables virus replication. In: 26th International Herpesvirus Workshop. Regensburg, Germany, 2001.Google Scholar
  121. 119a.
    Reboredo M, Greaves RF, Hahn G. Human cytomegalovirusproteins encoded by UL37 exon 1 protect infected fibrob-lasts against virus-induced apoptosis and are required for efficient virus replication. J Gen Virol 2004; 85: 3555–3567.PubMedGoogle Scholar
  122. 120.
    Braud VM, Tomasec P, Wilkinson GW. Viral evasion of natural killer cells during human cytomegalovirus infection. Curr Top Microbiol Immunol 2002; 269: 117–129.PubMedGoogle Scholar
  123. 121.
    Arase H, Mocarski ES, Campbell AE, et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 2002; 296: 1323–1326.PubMedGoogle Scholar
  124. 122.
    Wang EC, Borysiewicz LK. The role of CD8+, CD57+ cells in human cytomegalovirus and other viral infections. Scand J Infect Dis Suppl 1995; 99: 69–77.PubMedGoogle Scholar
  125. 123.
    Oshimi Y, Oda S, Honda Y, et al. Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. J Immunol 1996; 157: 2909–2915.PubMedGoogle Scholar
  126. 124.
    Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 1449–1456.PubMedGoogle Scholar
  127. 125.
    Patterson CE, Shenk T. Human cytomegalovirus UL36 protein is dispensable for viral replication in cultured cells. J Virol 1999; 73: 7126–7131.PubMedGoogle Scholar
  128. 126.
    Sequar G, Britt WJ, Lakeman FD, et al. Experimental coinfection of rhesus macaques with rhesus cytomegalovirus and simian immunodeficiency virus: Pathogenesis. J Virol 2002; 76: 7661–7671.CrossRefPubMedGoogle Scholar
  129. 127.
    Lockridge KM, Sequar G, Zhou SS, et al. Pathogenesis of experimental rhesus cytomegalovirus infection. J Virol 1999; 73: 9576–9583.PubMedGoogle Scholar
  130. 127a.
    Varnum SM, Streblow DN, Monroe ME,et al. Identifica-tion of proteins in human cytomegalovirus (HCMV) par-ticles: The HCMV proteome.J Virol 2004; 78: 10960–10966.CrossRefPubMedGoogle Scholar
  131. 127b.
    Kattenhorn LM, Mills R, Wagner M, et al. Identification of proteins associated with murine cytomegalovirus virions. J Virol 22004; 78: 11187–11197.Google Scholar
  132. 128.
    Mocarski ES, Courcelle CT. In: (KD M., Howley PM, eds). Fields Virology New York: Lippincott-Raven, 2001: 2629–2673.Google Scholar
  133. 129.
    Colberg-Poley AM. Functional roles of immediate early proteins encoded by the human cytomegalovirus UL36-38, UL115-119, TRS1/IRS1 and US3 loci. Intervirology 1996; 39: 350–360.PubMedGoogle Scholar
  134. 130.
    Bertin J, Armstrong RC, Ottilie S, et al. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci USA 1997; 94: 1172–1176.PubMedGoogle Scholar
  135. 131.
    Medici MA, Sciortino MT, Perri D, et al. Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis: Role of nuclear factor kappaB. J Biol Chem 2003; 278: 36059–36067.CrossRefPubMedGoogle Scholar
  136. 132.
    Munger J, Roizman B. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc Natl Acad Sci USA 2001; 98: 10410–10415.PubMedGoogle Scholar
  137. 133.
    Peng W, Henderson G, Perng GC, et al. The gene that encodes the herpes simplex virus type 1 latency-associated transcript influences the accumulation of transcripts (Bcl-x(L) and Bcl-x(S)) that encode apoptotic regulatory proteins. J Virol 2003; 77: 10714–10718.PubMedGoogle Scholar
  138. 134.
    Benetti L, Munger J, Roizman B. The herpes simplex virus 1 US3 protein kinase blocks caspase-dependent double cleavage and activation of the proapoptotic protein BAD. J Virol 2003; 77: 6567–65673.PubMedGoogle Scholar
  139. 135.
    Yamauchi Y, Daikoku T, Goshima F, et al. Herpes simplex virus UL14 protein blocks apoptosis. Microbiol Immunol 2003; 47: 685–689.PubMedGoogle Scholar
  140. 136.
    Aubert M, Rice SA, Blaho JA. Accumulation of herpes simplex virus type 1 early and leaky-late proteins correlates with apoptosis prevention in infected human HEp-2 cells. J Virol 2001; 75: 1013–1030.PubMedGoogle Scholar
  141. 137.
    Aubert M, Blaho JA. The herpes simplex virus type 1 regulatory protein ICP27 is required for the prevention of apoptosis in infected human cells. J Virol 1999; 73: 2803–2813.PubMedGoogle Scholar
  142. 138.
    Jerome KR, Fox R, Chen Z, et al. Herpes simplex virus inhibits apoptosis through the action of two genes, Us5 and Us3. J Virol 1999; 73: 8950–8957.PubMedGoogle Scholar
  143. 139.
    Leopardi R, Roizman B. The herpes simplex virus major regulatory protein ICP4 blocks apoptosis induced by the virus or by hyperthermia. Proc Natl Acad Sci USA 1996; 93: 9583&9587.PubMedGoogle Scholar
  144. 140.
    He Q, Montalbano J, Corcoran C, et al. Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis. Oncogene 2003; 22: 2674–2679.PubMedGoogle Scholar
  145. 141.
    Juin P, Hunt A, Littlewood T, et al. c-Myc functionally cooperates with Bax to induce apoptosis. Mol Cell Biol 2002; 22: 6158–6169.PubMedGoogle Scholar
  146. 142.
    Eischen CM, Roussel MF, Korsmeyer SJ, et al. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol 2001; 21: 7653–7662.PubMedGoogle Scholar
  147. 143.
    Brustovetsky N, Dubinsky JM, Antonsson B, et al. Two pathways for tBID-induced cytochrome c release from rat brain mitochondria: BAK- versus BAX-dependence. J Neurochem 2003; 84: 196–207.PubMedGoogle Scholar
  148. 144.
    Cuconati A, Degenhardt K, Sundararajan R, et al. Bak and Bax function to limit adenovirus replication through apoptosis induction. J Virol 2002; 76: 4547–4558.PubMedGoogle Scholar
  149. 145.
    Degenhardt K, Sundararajan R, Lindsten T, et al. Bax and Bak independently promote cytochrome C release from mitochondria. J Biol Chem 2002; 277: 14127–14134.PubMedGoogle Scholar
  150. 146.
    Wang GQ, Gastman BR, Wieckowski E, et al. A role for mitochondrial Bak in apoptotic response to anticancer drugs. J Biol Chem 2001; 276: 34307–34317.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.ImmunoGen, Inc.CambridgeUSA

Personalised recommendations