Kaposi’s Sarcoma-Associated Herpesvirus: Pathogenesis and Host Immune Response

Chapter

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 or HHV-8 is a member of the family of gammaherpesviruses. The virus was first discovered by Drs. Yuan Chang and Patrick Moore in 1994 in Kaposi sarcoma lesions from HIV-infected individuals. This virus is also associated with two lymphoproliferative diseases, named primary effusion lymphoma and multicentric Castleman’s disease. In this chapter, we describe aspects of the latent and lytic phases of the KSHV lifecycle. We also discuss the function of different viral genes that help the virus survive in the infected host.

Keywords

Migration Lymphoma Tyrosine Heparin Germinal 

Notes

Acknowledgments

We thank the Damania lab members for helpful discussions. B.D. is supported by NIH grants CA096500, 019014, AI107810, AI109965, DE018281, and DE023946. B.D. is a Leukemia & Lymphoma Society Scholar and a Burroughs Wellcome Fund Investigator in Infectious Disease. Due to space constraints, we apologize for not referencing many other publications in this chapter.

References

  1. 1.
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266(5192):1865–9.PubMedGoogle Scholar
  2. 2.
    Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995;332(18):1186–91.PubMedGoogle Scholar
  3. 3.
    Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86(4):1276–80.PubMedGoogle Scholar
  4. 4.
    Uldrick TS, Wang V, O’Mahony D, Aleman K, Wyvill KM, Marshall V, et al. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease. Clin Infect Dis. 2010;51(3):350–8. Epub 2010/06/30.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol. 2012;3:73. Epub 2012/03/10.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P. Biology of Kaposi’s sarcoma. Eur J Cancer. 2001;37(10):1251–69.PubMedGoogle Scholar
  7. 7.
    Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Makinen T, et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet. 2004;36(7):687–93.PubMedGoogle Scholar
  8. 8.
    Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, et al. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet. 2004;36(7):683–5.PubMedGoogle Scholar
  9. 9.
    Carroll PA, Brazeau E, Lagunoff M. Kaposi’s sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology. 2004;328(1):7–18.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Hansen A, Henderson S, Lagos D, Nikitenko L, Coulter E, Roberts S, et al. KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming. Genes Dev. 2010;24(2):195–205.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Kaposi M. Idiopathisches multiples Pigmentsarkom der Haut. Arch Dermatol Syph. 1872;4:265–73.Google Scholar
  12. 12.
    Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med. 2000;342(14):1027–38.PubMedGoogle Scholar
  13. 13.
    Herndier B, Ganem D. The biology of Kaposi’s sarcoma. Cancer Treat Res. 2001;104:89–126.PubMedGoogle Scholar
  14. 14.
    Green I, Espiritu E, Ladanyi M, Chaponda R, Wieczorek R, Gallo L, et al. Primary lymphomatous effusions in AIDS: a morphological, immunophenotypic, and molecular study. Mod Pathol. 1995;8(1):39–45.PubMedGoogle Scholar
  15. 15.
    Knowles DM, Inghirami G, Ubriaco A, Dalla-Favera R. Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood. 1989;73(3):792–9.PubMedGoogle Scholar
  16. 16.
    Du MQ, Liu H, Diss TC, Ye H, Hamoudi RA, Dupin N, et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood. 2001;97(7):2130–6.PubMedGoogle Scholar
  17. 17.
    Zhu FX, Chong JM, Wu L, Yuan Y. Virion proteins of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2005;79(2):800–11.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Bechtel JT, Winant RC, Ganem D. Host and viral proteins in the virion of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2005;79(8):4952–64.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Bechtel J, Grundhoff A, Ganem D. RNAs in the virion of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2005;79(16):10138–46.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Trus BL, Heymann JB, Nealon K, Cheng N, Newcomb WW, Brown JC, et al. Capsid structure of Kaposi’s sarcoma-associated herpesvirus, a gammaherpesvirus, compared to those of an alphaherpesvirus, herpes simplex virus type 1, and a betaherpesvirus, cytomegalovirus. J Virol. 2001;75(6):2879–90.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Nealon K, Newcomb WW, Pray TR, Craik CS, Brown JC, Kedes DH. Lytic replication of Kaposi’s sarcoma-associated herpesvirus results in the formation of multiple capsid species: isolation and molecular characterization of A, B, and C capsids from a gammaherpesvirus. J Virol. 2001;75(6):2866–78.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Wu L, Lo P, Yu X, Stoops JK, Forghani B, Zhou ZH. Three-dimensional structure of the human herpesvirus 8 capsid. J Virol. 2000;74(20):9646–54.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Deng B, O’Connor CM, Kedes DH, Zhou ZH. Cryo-electron tomography of Kaposi’s sarcoma-associated herpesvirus capsids reveals dynamic scaffolding structures essential to capsid assembly and maturation. J Struct Biol. 2008;161(3):419–27.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Deng B, O’Connor CM, Kedes DH, Zhou ZH. Direct visualization of the putative portal in the Kaposi’s sarcoma-associated herpesvirus capsid by cryoelectron tomography. J Virol. 2007;81(7):3640–4.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Perkins EM, Anacker D, Davis A, Sankar V, Ambinder RF, Desai P. Small capsid protein pORF65 is essential for assembly of Kaposi’s sarcoma-associated herpesvirus capsids. J Virol. 2008;82(14):7201–11. Epub 2008/05/09.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Renne R, Lagunoff M, Zhong W, Ganem D. The size and conformation of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol. 1996;70(11):8151–4.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Neipel F, Albrecht JC, Fleckenstein B. Human herpesvirus 8–the first human Rhadinovirus. J Natl Cancer Inst Monogr. 1998;23:73–7.PubMedGoogle Scholar
  28. 28.
    Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, et al. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A. 1996;93(25):14862–7.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Neipel F, Albrecht JC, Fleckenstein B. Cell-homologous genes in the Kaposi’s sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J Virol. 1997;71(6):4187–92.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Pfeffer S, Sewer A, Lagos-Quintana M, Sheridan R, Sander C, Grasser FA, et al. Identification of microRNAs of the herpesvirus family. Nat Methods. 2005;2(4):269–76.PubMedGoogle Scholar
  31. 31.
    Samols MA, Hu J, Skalsky RL, Renne R. Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2005;79(14):9301–5.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Cai X, Lu S, Zhang Z, Gonzalez CM, Damania B, Cullen BR. Kaposi’s sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci U S A. 2005;102(15):5570–5.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Conrad NK, Steitz JA. A Kaposi’s sarcoma virus RNA element that increases the nuclear abundance of intronless transcripts. EMBO J. 2005;24(10):1831–41.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Sun R, Lin SF, Gradoville L, Miller G. Polyadenylylated nuclear RNA encoded by Kaposi sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A. 1996;93(21):11883–8.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Zhong W, Wang H, Herndier B, Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A. 1996;93(13):6641–6.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Zhong W, Ganem D. Characterization of ribonucleoprotein complexes containing an abundant polyadenylated nuclear RNA encoded by Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8). J Virol. 1997;71(2):1207–12.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Pertel PE. Human herpesvirus 8 glycoprotein B (gB), gH, and gL can mediate cell fusion. J Virol. 2002;76(9):4390–400.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Akula SM, Wang FZ, Vieira J, Chandran B. Human herpesvirus 8 interaction with target cells involves heparan sulfate. Virology. 2001;282(2):245–55.PubMedGoogle Scholar
  39. 39.
    Wang FZ, Akula SM, Sharma-Walia N, Zeng L, Chandran B. Human herpesvirus 8 envelope glycoprotein B mediates cell adhesion via its RGD sequence. J Virol. 2003;77(5):3131–47.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Naranatt PP, Akula SM, Zien CA, Krishnan HH, Chandran B. Kaposi’s sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol. 2003;77(2):1524–39.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Hahn A, Birkmann A, Wies E, Dorer D, Mahr K, Sturzl M, et al. Kaposi’s sarcoma-associated herpesvirus gH/gL: glycoprotein export and interaction with cellular receptors. J Virol. 2009;83(1):396–407.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Birkmann A, Mahr K, Ensser A, Yaguboglu S, Titgemeyer F, Fleckenstein B, et al. Cell surface heparan sulfate is a receptor for human herpesvirus 8 and interacts with envelope glycoprotein K8.1. J Virol. 2001;75(23):11583–93.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Akula SM, Pramod NP, Wang FZ, Chandran B. Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell. 2002;108(3):407–19.PubMedGoogle Scholar
  44. 44.
    Garrigues HJ, Rubinchikova YE, Dipersio CM, Rose TM. Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of Kaposi’s sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor. J Virol. 2008;82(3):1570–80.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Rappocciolo G, Hensler HR, Jais M, Reinhart TA, Pegu A, Jenkins FJ, et al. Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN. J Virol. 2008;82(10):4793–806.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Rappocciolo G, Jenkins FJ, Hensler HR, Piazza P, Jais M, Borowski L, et al. DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. J Immunol. 2006;176(3):1741–9.PubMedGoogle Scholar
  47. 47.
    Kaleeba JA, Berger EA. Kaposi’s sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT. Science. 2006;311(5769):1921–4.PubMedGoogle Scholar
  48. 48.
    Hahn AS, Kaufmann JK, Wies E, Naschberger E, Panteleev-Ivlev J, Schmidt K, et al. The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus. Nat Med. 2012;18(6):961–6. Epub 2012/05/29.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Chakraborty S, Veettil MV, Bottero V, Chandran B. Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc Natl Acad Sci U S A. 2012;109(19):E1163–72. Epub 2012/04/18.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Akula SM, Naranatt PP, Walia NS, Wang FZ, Fegley B, Chandran B. Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) infection of human fibroblast cells occurs through endocytosis. J Virol. 2003;77(14):7978–90.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Chandran B. Early events in Kaposi’s sarcoma-associated herpesvirus infection of target cells. J Virol. 2010;84(5):2188–99.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Raghu H, Sharma-Walia N, Veettil MV, Sadagopan S, Chandran B. Kaposi’s sarcoma-associated herpesvirus utilizes an actin polymerization-dependent macropinocytic pathway to enter human dermal microvascular endothelial and human umbilical vein endothelial cells. J Virol. 2009;83(10):4895–911.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Valiya Veettil M, Sadagopan S, Kerur N, Chakraborty S, Chandran B. Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi’s sarcoma-associated herpesvirus. PLoS Pathog. 2010;6(12):e1001238.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Krishnan HH, Sharma-Walia N, Streblow DN, Naranatt PP, Chandran B. Focal adhesion kinase is critical for entry of Kaposi’s sarcoma-associated herpesvirus into target cells. J Virol. 2006;80(3):1167–80.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Raghu H, Sharma-Walia N, Veettil MV, Sadagopan S, Caballero A, Sivakumar R, et al. Lipid rafts of primary endothelial cells are essential for Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8-induced phosphatidylinositol 3-kinase and RhoA-GTPases critical for microtubule dynamics and nuclear delivery of viral DNA but dispensable for binding and entry. J Virol. 2007;81(15):7941–59.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Pan H, Xie J, Ye F, Gao SJ. Modulation of Kaposi’s sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J Virol. 2006;80(11):5371–82.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Naranatt PP, Krishnan HH, Smith MS, Chandran B. Kaposi’s sarcoma-associated herpesvirus modulates microtubule dynamics via RhoA-GTP-diaphanous 2 signaling and utilizes the dynein motors to deliver its DNA to the nucleus. J Virol. 2005;79(2):1191–206.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B. ERK1/2 and MEK1/2 induced by Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol. 2005;79(16):10308–29.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Sharma-Walia N, Naranatt PP, Krishnan HH, Zeng L, Chandran B. Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein gB induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements. J Virol. 2004;78(8):4207–23.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Sadagopan S, Sharma-Walia N, Veettil MV, Raghu H, Sivakumar R, Bottero V, et al. Kaposi’s sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression. J Virol. 2007;81(8):3949–68.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Veettil MV, Sharma-Walia N, Sadagopan S, Raghu H, Sivakumar R, Naranatt PP, et al. RhoA-GTPase facilitates entry of Kaposi’s sarcoma-associated herpesvirus into adherent target cells in a Src-dependent manner. J Virol. 2006;80(23):11432–46.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Xie J, Pan H, Yoo S, Gao SJ. Kaposi’s sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol. 2005;79(24):15027–37.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Yoo SM, Zhou FC, Ye FC, Pan HY, Gao SJ. Early and sustained expression of latent and host modulating genes in coordinated transcriptional program of KSHV productive primary infection of human primary endothelial cells. Virology. 2005;343(1):47–64.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Naranatt PP, Krishnan HH, Svojanovsky SR, Bloomer C, Mathur S, Chandran B. Host gene induction and transcriptional reprogramming in Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8)-infected endothelial, fibroblast, and B cells: insights into modulation events early during infection. Cancer Res. 2004;64(1):72–84.PubMedGoogle Scholar
  65. 65.
    West JA, Gregory SM, Sivaraman V, Su L, Damania B. Activation of plasmacytoid dendritic cells by Kaposi’s sarcoma-associated herpesvirus. J Virol. 2011;85(2):895–904.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Greene W, Gao SJ. Actin dynamics regulate multiple endosomal steps during Kaposi’s sarcoma-associated herpesvirus entry and trafficking in endothelial cells. PLoS Pathog. 2009;5(7):e1000512.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Inoue N, Winter J, Lal RB, Offermann MK, Koyano S. Characterization of entry mechanisms of human herpesvirus 8 by using an Rta-dependent reporter cell line. J Virol. 2003;77(14):8147–52.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Jarousse N, Chandran B, Coscoy L. Lack of heparan sulfate expression in B-cell lines: implications for Kaposi’s sarcoma-associated herpesvirus and murine gammaherpesvirus 68 infections. J Virol. 2008;82(24):12591–7.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Kaleeba JA, Berger EA. Broad target cell selectivity of Kaposi’s sarcoma-associated herpesvirus glycoprotein-mediated cell fusion and virion entry. Virology. 2006;354(1):7–14.PubMedGoogle Scholar
  70. 70.
    Kliche S, Kremmer E, Hammerschmidt W, Koszinowski U, Haas J. Persistent infection of Epstein-Barr virus-positive B lymphocytes by human herpesvirus 8. J Virol. 1998;72(10):8143–9.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Krishnan HH, Naranatt PP, Smith MS, Zeng L, Bloomer C, Chandran B. Concurrent expression of latent and a limited number of lytic genes with immune modulation and antiapoptotic function by Kaposi’s sarcoma-associated herpesvirus early during infection of primary endothelial and fibroblast cells and subsequent decline of lytic gene expression. J Virol. 2004;78(7):3601–20.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Lagunoff M, Bechtel J, Venetsanakos E, Roy AM, Abbey N, Herndier B, et al. De novo infection and serial transmission of Kaposi’s sarcoma-associated herpesvirus in cultured endothelial cells. J Virol. 2002;76(5):2440–8.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Renne R, Blackbourn D, Whitby D, Levy J, Ganem D. Limited transmission of Kaposi’s sarcoma-associated herpesvirus in cultured cells. J Virol. 1998;72(6):5182–8.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Hassman LM, Ellison TJ, Kedes DH. KSHV infects a subset of human tonsillar B cells, driving proliferation and plasmablast differentiation. J Clin Invest. 2011;121(2):752–68.PubMedCentralPubMedGoogle Scholar
  75. 75.
    West J, Damania B. Upregulation of the TLR3 pathway by Kaposi’s sarcoma-associated herpesvirus during primary infection. J Virol. 2008;82(11):5440–9.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Ambroziak JA, Blackbourn DJ, Herndier BG, Glogau RG, Gullett JH, McDonald AR, et al. Herpes-like sequences in HIV-infected and uninfected Kaposi’s sarcoma patients. Science. 1995;268(5210):582–3.PubMedGoogle Scholar
  77. 77.
    Dupin N, Fisher C, Kellam P, Ariad S, Tulliez M, Franck N, et al. Distribution of human herpesvirus-8 latently infected cells in Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A. 1999;96(8):4546–51.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Parravicini C, Chandran B, Corbellino M, Berti E, Paulli M, Moore PS, et al. Differential viral protein expression in Kaposi’s sarcoma-associated herpesvirus-infected diseases: Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Am J Pathol. 2000;156(3):743–9.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Foreman KE, Bacon PE, Hsi ED, Nickoloff BJ. In situ polymerase chain reaction-based localization studies support role of human herpesvirus-8 as the cause of two AIDS-related neoplasms: Kaposi’s sarcoma and body cavity lymphoma. J Clin Invest. 1997;99(12):2971–8. Epub 1997/06/15.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Reed JA, Nador RG, Spaulding D, Tani Y, Cesarman E, Knowles DM. Demonstration of Kaposi’s sarcoma-associated herpes virus cyclin D homolog in cutaneous Kaposi’s sarcoma by colorimetric in situ hybridization using a catalyzed signal amplification system. Blood. 1998;91(10):3825–32. Epub 1998/06/20.PubMedGoogle Scholar
  81. 81.
    Staskus KA, Zhong W, Gebhard K, Herndier B, Wang H, Renne R, et al. Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol. 1997;71(1):715–9. Epub 1997/01/01.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Blasig C, Zietz C, Haar B, Neipel F, Esser S, Brockmeyer NH, et al. Monocytes in Kaposi’s sarcoma lesions are productively infected by human herpesvirus 8. J Virol. 1997;71(10):7963–8.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G. A viral gene that activates lytic cycle expression of Kaposi’s sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A. 1998;95(18):10866–71.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Lukac DM, Kirshner JR, Ganem D. Transcriptional activation by the product of open reading frame 50 of Kaposi’s sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. J Virol. 1999;73(11):9348–61.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Yu Y, Black JB, Goldsmith CS, Browning PJ, Bhalla K, Offermann MK. Induction of human herpesvirus-8 DNA replication and transcription by butyrate and TPA in BCBL-1 cells. J Gen Virol. 1999;80(Pt 1):83–90.PubMedGoogle Scholar
  86. 86.
    Mercader M, Taddeo B, Panella JR, Chandran B, Nickoloff BJ, Foreman KE. Induction of HHV-8 lytic cycle replication by inflammatory cytokines produced by HIV-1-infected T cells. Am J Pathol. 2000;156(6):1961–71.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Chang J, Renne R, Dittmer D, Ganem D. Inflammatory cytokines and the reactivation of Kaposi’s sarcoma-associated herpesvirus lytic replication. Virology. 2000;266(1):17–25.PubMedGoogle Scholar
  88. 88.
    Wilson SJ, Tsao EH, Webb BL, Ye H, Dalton-Griffin L, Tsantoulas C, et al. X box binding protein XBP-1s transactivates the Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency. J Virol. 2007;81(24):13578–86.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Yu F, Feng J, Harada JN, Chanda SK, Kenney SC, Sun R. B cell terminal differentiation factor XBP-1 induces reactivation of Kaposi’s sarcoma-associated herpesvirus. FEBS Lett. 2007;581(18):3485–8.PubMedGoogle Scholar
  90. 90.
    Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll-like receptor signaling controls reactivation of KSHV from latency. Proc Natl Acad Sci U S A. 2009;106(28):11725–30.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Dillon PJ, Gregory SM, Tamburro K, Sanders MK, Johnson GL, Raab-Traub N, et al. Tousled-like kinases modulate reactivation of gammaherpesviruses from latency. Cell Host Microbe. 2013;13(2):204–14. Epub 2013/02/19.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Chen HS, Wikramasinghe P, Showe L, Lieberman PM. Cohesins repress Kaposi’s sarcoma-associated herpesvirus immediate early gene transcription during latency. J Virol. 2012;86(17):9454–64. Epub 2012/06/29.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Vieira J, Huang ML, Koelle DM, Corey L. Transmissible Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) in saliva of men with a history of Kaposi’s sarcoma. J Virol. 1997;71(9):7083–7.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Pauk J, Huang ML, Brodie SJ, Wald A, Koelle DM, Schacker T, et al. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med. 2000;343(19):1369–77.PubMedGoogle Scholar
  95. 95.
    Casper C, Redman M, Huang ML, Pauk J, Lampinen TM, Hawes SE, et al. HIV infection and human herpesvirus-8 oral shedding among men who have sex with men. J Acquir Immune Defic Syndr. 2004;35(3):233–8.PubMedGoogle Scholar
  96. 96.
    Duus KM, Lentchitsky V, Wagenaar T, Grose C, Webster-Cyriaque J. Wild-type Kaposi’s sarcoma-associated herpesvirus isolated from the oropharynx of immune-competent individuals has tropism for cultured oral epithelial cells. J Virol. 2004;78(8):4074–84.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Casper C, Krantz E, Selke S, Kuntz SR, Wang J, Huang ML, et al. Frequent and asymptomatic oropharyngeal shedding of human herpesvirus 8 among immunocompetent men. J Infect Dis. 2007;195(1):30–6. Epub 2006/12/08.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Dittmer D, Lagunoff M, Renne R, Staskus K, Haase A, Ganem D. A cluster of latently expressed genes in Kaposi’s sarcoma-associated herpesvirus. J Virol. 1998;72(10):8309–15.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. Transcription mapping of the Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J Virol. 1998;72(2):1005–12.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Talbot SJ, Weiss RA, Kellam P, Boshoff C. Transcriptional analysis of human herpesvirus-8 open reading frames 71, 72, 73, K14, and 74 in a primary effusion lymphoma cell line. Virology. 1999;257(1):84–94.PubMedGoogle Scholar
  101. 101.
    Pearce M, Matsumura S, Wilson AC. Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi’s sarcoma-associated herpesvirus originate from a common promoter. J Virol. 2005;79(22):14457–64.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Cai X, Cullen BR. Transcriptional origin of Kaposi’s sarcoma-associated herpesvirus microRNAs. J Virol. 2006;80(5):2234–42.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Grundhoff A, Sullivan CS, Ganem D. A combined computational and microarray-based approach identifies novel microRNAs encoded by human gamma-herpesviruses. RNA. 2006;12(5):733–50.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Fakhari FD, Dittmer DP. Charting latency transcripts in Kaposi’s sarcoma-associated herpesvirus by whole-genome real-time quantitative PCR. J Virol. 2002;76(12):6213–23.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Dittmer DP. Transcription profile of Kaposi’s sarcoma-associated herpesvirus in primary Kaposi’s sarcoma lesions as determined by real-time PCR arrays. Cancer Res. 2003;63(9):2010–5.PubMedGoogle Scholar
  106. 106.
    Rivas C, Thlick AE, Parravicini C, Moore PS, Chang Y. Kaposi’s sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. J Virol. 2001;75(1):429–38.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Ballestas ME, Chatis PA, Kaye KM. Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science. 1999;284(5414):641–4.PubMedGoogle Scholar
  108. 108.
    Ballestas ME, Kaye KM. Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J Virol. 2001;75(7):3250–8.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Cotter 2nd MA, Robertson ES. The latency-associated nuclear antigen tethers the Kaposi’s sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology. 1999;264(2):254–64.PubMedGoogle Scholar
  110. 110.
    Cotter 2nd MA, Subramanian C, Robertson ES. The Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen binds to specific sequences at the left end of the viral genome through its carboxy-terminus. Virology. 2001;291(2):241–59.PubMedGoogle Scholar
  111. 111.
    Garber AC, Hu J, Renne R. Latency-associated nuclear antigen (LANA) cooperatively binds to two sites within the terminal repeat, and both sites contribute to the ability of LANA to suppress transcription and to facilitate DNA replication. J Biol Chem. 2002;277(30):27401–11.PubMedGoogle Scholar
  112. 112.
    Garber AC, Shu MA, Hu J, Renne R. DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2001;75(17):7882–92.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Barbera AJ, Ballestas ME, Kaye KM. The Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen 1N terminus is essential for chromosome association, DNA replication, and episome persistence. J Virol. 2004;78(1):294–301.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Piolot T, Tramier M, Coppey M, Nicolas JC, Marechal V. Close but distinct regions of human herpesvirus 8 latency-associated nuclear antigen 1 are responsible for nuclear targeting and binding to human mitotic chromosomes. J Virol. 2001;75(8):3948–59.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Joukov V, Walter JC, Luger K, et al. The nucleosomal surface as a docking station for Kaposi’s sarcoma herpesvirus LANA. Science. 2006;311(5762):856–61.PubMedGoogle Scholar
  116. 116.
    Watanabe T, Sugaya M, Atkins AM, Aquilino EA, Yang A, Borris DL, et al. Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen prolongs the life span of primary human umbilical vein endothelial cells. J Virol. 2003;77(11):6188–96.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Fakhari FD, Jeong JH, Kanan Y, Dittmer DP. The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma. J Clin Invest. 2006;116(3):735–42.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Sin SH, Fakhari FD, Dittmer DP. The viral latency-associated nuclear antigen augments the B-cell response to antigen in vivo. J Virol. 2010;84(20):10653–60.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Friborg Jr J, Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature. 1999;402(6764):889–94.PubMedGoogle Scholar
  120. 120.
    Petre CE, Sin SH, Dittmer DP. Functional p53 signaling in Kaposi’s sarcoma-associated herpesvirus lymphomas: implications for therapy. J Virol. 2007;81(4):1912–22.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Radkov SA, Kellam P, Boshoff C. The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nat Med. 2000;6(10):1121–7.PubMedGoogle Scholar
  122. 122.
    Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS, et al. A novel viral mechanism for dysregulation of beta-catenin in Kaposi’s sarcoma-associated herpesvirus latency. Nat Med. 2003;9(3):300–6.PubMedGoogle Scholar
  123. 123.
    Bubman D, Guasparri I, Cesarman E. Deregulation of c-Myc in primary effusion lymphoma by Kaposi’s sarcoma herpesvirus latency-associated nuclear antigen. Oncogene. 2007;26(34):4979–86.PubMedGoogle Scholar
  124. 124.
    Liu J, Martin HJ, Liao G, Hayward SD. The Kaposi’s sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol. 2007;81(19):10451–9.PubMedCentralPubMedGoogle Scholar
  125. 125.
    Sun Z, Xiao B, Jha HC, Lu J, Banerjee S, Robertson ES. KSHV encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1. J Virol. 2014. Epub 2014/04/18.Google Scholar
  126. 126.
    Renne R, Barry C, Dittmer D, Compitello N, Brown PO, Ganem D. Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2001;75(1):458–68.PubMedCentralPubMedGoogle Scholar
  127. 127.
    An FQ, Compitello N, Horwitz E, Sramkoski M, Knudsen ES, Renne R. The latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest. J Biol Chem. 2005;280(5):3862–74.PubMedGoogle Scholar
  128. 128.
    Wong LY, Matchett GA, Wilson AC. Transcriptional activation by the Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen is facilitated by an N-terminal chromatin-binding motif. J Virol. 2004;78(18):10074–85.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Krithivas A, Young DB, Liao G, Greene D, Hayward SD. Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein-Barr virus gene expression in dually infected PEL cells. J Virol. 2000;74(20):9637–45.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Schwam DR, Luciano RL, Mahajan SS, Wong L, Wilson AC. Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies. J Virol. 2000;74(18):8532–40.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Lan K, Kuppers DA, Robertson ES. Kaposi’s sarcoma-associated herpesvirus reactivation is regulated by interaction of latency-associated nuclear antigen with recombination signal sequence-binding protein Jkappa, the major downstream effector of the Notch signaling pathway. J Virol. 2005;79(6):3468–78.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Cai Q, Cai S, Zhu C, Verma SC, Choi JY, Robertson ES. A unique SUMO-2-interacting motif within LANA is essential for KSHV latency. PLoS Pathog. 2013;9(11):e1003750. Epub 2013/11/28.PubMedCentralPubMedGoogle Scholar
  133. 133.
    Sun R, Liang D, Gao Y, Lan K. Kaposi’s sarcoma-associated herpesvirus-encoded LANA interacts with host KAP1 to facilitate establishment of viral latency. J Virol. 2014. Epub 2014/04/18.Google Scholar
  134. 134.
    Chang Y, Moore PS, Talbot SJ, Boshoff CH, Zarkowska T, Godden K, et al. Cyclin encoded by KS herpesvirus. Nature. 1996;382(6590):410.PubMedGoogle Scholar
  135. 135.
    Godden-Kent D, Talbot SJ, Boshoff C, Chang Y, Moore P, Weiss RA, et al. The cyclin encoded by Kaposi’s sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. J Virol. 1997;71(6):4193–8.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Li M, Lee H, Yoon DW, Albrecht JC, Fleckenstein B, Neipel F, et al. Kaposi’s sarcoma-associated herpesvirus encodes a functional cyclin. J Virol. 1997;71(3):1984–91.PubMedCentralPubMedGoogle Scholar
  137. 137.
    Cuomo ME, Knebel A, Morrice N, Paterson H, Cohen P, Mittnacht S. p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. Nat Cell Biol. 2008;10(6):723–30.PubMedGoogle Scholar
  138. 138.
    Swanton C, Mann DJ, Fleckenstein B, Neipel F, Peters G, Jones N. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature. 1997;390(6656):184–7.PubMedGoogle Scholar
  139. 139.
    Mann DJ, Child ES, Swanton C, Laman H, Jones N. Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi’s sarcoma-associated herpesvirus. EMBO J. 1999;18(3):654–63.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Ellis M, Chew YP, Fallis L, Freddersdorf S, Boshoff C, Weiss RA, et al. Degradation of p27(Kip) cdk inhibitor triggered by Kaposi’s sarcoma virus cyclin-cdk6 complex. EMBO J. 1999;18(3):644–53.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Zhi H, Zahoor MA, Shudofsky AM, Giam CZ. KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-kappaB hyperactivation. Oncogene. 2014. Epub 2014/01/29.Google Scholar
  142. 142.
    Chang PC, Li M. Kaposi’s sarcoma-associated herpesvirus K-cyclin interacts with Cdk9 and stimulates Cdk9-mediated phosphorylation of p53 tumor suppressor. J Virol. 2008;82(1):278–90.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Verschuren EW, Hodgson JG, Gray JW, Kogan S, Jones N, Evan GI. The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. Cancer Res. 2004;64(2):581–9.PubMedGoogle Scholar
  144. 144.
    Verschuren EW, Klefstrom J, Evan GI, Jones N. The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell. 2002;2(3):229–41.PubMedGoogle Scholar
  145. 145.
    Sugaya M, Watanabe T, Yang A, Starost MF, Kobayashi H, Atkins AM, et al. Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter. Blood. 2005;105(6):2356–63.PubMedGoogle Scholar
  146. 146.
    Jones T, Ramos da Silva S, Bedolla R, Ye F, Zhou F, Gao SJ. Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition. Cell Cycle. 2014;13(5):845–58. Epub 2014/01/15.PubMedGoogle Scholar
  147. 147.
    Belanger C, Gravel A, Tomoiu A, Janelle ME, Gosselin J, Tremblay MJ, et al. Human herpesvirus 8 viral FLICE-inhibitory protein inhibits Fas-mediated apoptosis through binding and prevention of procaspase-8 maturation. J Hum Virol. 2001;4(2):62–73.PubMedGoogle Scholar
  148. 148.
    Djerbi M, Screpanti V, Catrina AI, Bogen B, Biberfeld P, Grandien A. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med. 1999;190(7):1025–32.PubMedCentralPubMedGoogle Scholar
  149. 149.
    Ballon G, Chen K, Perez R, Tam W, Cesarman E. Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest. 2011;121(3):1141–53.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Chugh P, Matta H, Schamus S, Zachariah S, Kumar A, Richardson JA, et al. Constitutive NF-kappaB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8K13 transgenic mice. Proc Natl Acad Sci U S A. 2005;102(36):12885–90.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Sun Q, Zachariah S, Chaudhary PM. The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-kappaB activation. J Biol Chem. 2003;278(52):52437–45.PubMedGoogle Scholar
  152. 152.
    Matta H, Sun Q, Moses G, Chaudhary PM. Molecular genetic analysis of human herpes virus 8-encoded viral FLICE inhibitory protein-induced NF-kappaB activation. J Biol Chem. 2003;278(52):52406–11.PubMedGoogle Scholar
  153. 153.
    Sun Q, Matta H, Chaudhary PM. The human herpes virus 8-encoded viral FLICE inhibitory protein protects against growth factor withdrawal-induced apoptosis via NF-kappa B activation. Blood. 2003;101(5):1956–61.PubMedGoogle Scholar
  154. 154.
    Chaudhary PM, Jasmin A, Eby MT, Hood L. Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene. 1999;18(42):5738–46.PubMedGoogle Scholar
  155. 155.
    Guasparri I, Keller SA, Cesarman E. KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med. 2004;199(7):993–1003.PubMedCentralPubMedGoogle Scholar
  156. 156.
    Field N, Low W, Daniels M, Howell S, Daviet L, Boshoff C, et al. KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci. 2003;116(Pt 18):3721–8.PubMedGoogle Scholar
  157. 157.
    Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem. 2002;277(16):13745–51.PubMedGoogle Scholar
  158. 158.
    Guasparri I, Wu H, Cesarman E. The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. EMBO Rep. 2006;7(1):114–9.PubMedCentralPubMedGoogle Scholar
  159. 159.
    Matta H, Chaudhary PM. Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc Natl Acad Sci U S A. 2004;101(25):9399–404.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Tolani B, Matta H, Gopalakrishnan R, Punj V, Chaudhary PM. NEMO is essential for KSHV-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death and its N-terminal 251 residues are sufficient for this process. J Virol. 2014. Epub 2014/03/29.Google Scholar
  161. 161.
    Forero A, Moore PS, Sarkar SN. Role of IRF4 in IFN-stimulated gene induction and maintenance of Kaposi sarcoma-associated herpesvirus latency in primary effusion lymphoma cells. J Immunol. 2013;191(3):1476–85. Epub 2013/06/28.PubMedGoogle Scholar
  162. 162.
    Singh VV, Kerur N, Bottero V, Dutta S, Chakraborty S, Ansari MA, et al. Kaposi’s sarcoma-associated herpesvirus latency in endothelial and B cells activates gamma interferon-inducible protein 16-mediated inflammasomes. J Virol. 2013;87(8):4417–31. Epub 2013/02/08.PubMedCentralPubMedGoogle Scholar
  163. 163.
    Graham C, Matta H, Yang Y, Yi H, Suo Y, Tolani B, et al. Kaposi’s sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor-induced growth arrest and apoptosis through NF-kappaB activation. J Virol. 2013;87(4):2242–52. Epub 2012/12/14.PubMedCentralPubMedGoogle Scholar
  164. 164.
    Ahmad A, Groshong JS, Matta H, Schamus S, Punj V, Robinson LJ, et al. Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 cooperates with Myc to promote lymphoma in mice. Cancer Biol Ther. 2010;10(10):1033–40.PubMedCentralPubMedGoogle Scholar
  165. 165.
    Sadler R, Wu L, Forghani B, Renne R, Zhong W, Herndier B, et al. A complex translational program generates multiple novel proteins from the latently expressed kaposin (K12) locus of Kaposi’s sarcoma-associated herpesvirus. J Virol. 1999;73(7):5722–30.PubMedCentralPubMedGoogle Scholar
  166. 166.
    Muralidhar S, Pumfery AM, Hassani M, Sadaie MR, Kishishita M, Brady JN, et al. Identification of kaposin (open reading frame K12) as a human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus) transforming gene. J Virol. 1998;72(6):4980–8.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Kliche S, Nagel W, Kremmer E, Atzler C, Ege A, Knorr T, et al. Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1. Mol Cell. 2001;7(4):833–43.PubMedGoogle Scholar
  168. 168.
    McCormick C, Ganem D. The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science. 2005;307(5710):739–41.PubMedGoogle Scholar
  169. 169.
    King CA. Kaposi's sarcoma-associated herpesvirus kaposin B induces unique monophosphorylation of STAT3 at serine 727 and MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28. J Virol. 2013;87(15):8779–91. Epub 2013/06/07.PubMedCentralPubMedGoogle Scholar
  170. 170.
    Umbach JL, Cullen BR. In-depth analysis of Kaposi’s sarcoma-associated herpesvirus microRNA expression provides insights into the mammalian microRNA-processing machinery. J Virol. 2010;84(2):695–703. Epub 2009/11/06.PubMedCentralPubMedGoogle Scholar
  171. 171.
    Bellare P, Ganem D. Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation. Cell Host Microbe. 2009;6(6):570–5.PubMedCentralPubMedGoogle Scholar
  172. 172.
    Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, Baker HV, et al. Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog. 2007;3(5):e65.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Skalsky RL, Samols MA, Plaisance KB, Boss IW, Riva A, Lopez MC, et al. Kaposi’s sarcoma-associated herpesvirus encodes an ortholog of miR-155. J Virol. 2007;81(23):12836–45.PubMedCentralPubMedGoogle Scholar
  174. 174.
    Gottwein E, Cullen BR. A human herpesvirus microRNA inhibits p21 expression and attenuates p21-mediated cell cycle arrest. J Virol. 2010;84(10):5229–37.PubMedCentralPubMedGoogle Scholar
  175. 175.
    Sin SH, Kim YB, Dittmer DP. Latency locus complements MicroRNA 155 deficiency in vivo. J Virol. 2013;87(21):11908–11. doi: 10.1128/JVI.01620-13. Epub 2013 Aug 21.PubMedCentralPubMedGoogle Scholar
  176. 176.
    Lei X, Bai Z, Ye F, Xie J, Kim CG, Huang Y, et al. Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol. 2010;12(2):193–9.PubMedCentralPubMedGoogle Scholar
  177. 177.
    Moody R, Zhu Y, Huang Y, Cui X, Jones T, Bedolla R, et al. KSHV microRNAs mediate cellular transformation and tumorigenesis by redundantly targeting cell growth and survival pathways. PLoS Pathog. 2013;9(12):e1003857. Epub 2014/01/05.PubMedCentralPubMedGoogle Scholar
  178. 178.
    Abend JR, Ramalingam D, Kieffer-Kwon P, Uldrick TS, Yarchoan R, Ziegelbauer JM. Kaposi's sarcoma-associated herpesvirus microRNAs target IRAK1 and MYD88, two components of the toll-like receptor/interleukin-1R signaling cascade, to reduce inflammatory-cytokine expression. J Virol. 2012;86(21):11663–74. Epub 2012/08/17.PubMedCentralPubMedGoogle Scholar
  179. 179.
    Gallaher AM, Das S, Xiao Z, Andresson T, Kieffer-Kwon P, Happel C, et al. Proteomic screening of human targets of viral microRNAs reveals functions associated with immune evasion and angiogenesis. PLoS Pathog. 2013;9(9):e1003584. Epub 2013/09/17.PubMedCentralPubMedGoogle Scholar
  180. 180.
    Gradoville L, Gerlach J, Grogan E, Shedd D, Nikiforow S, Metroka C, et al. Kaposi’s sarcoma-associated herpesvirus open reading frame 50/Rta protein activates the entire viral lytic cycle in the HH-B2 primary effusion lymphoma cell line. J Virol. 2000;74(13):6207–12.PubMedCentralPubMedGoogle Scholar
  181. 181.
    Lukac DM, Renne R, Kirshner JR, Ganem D. Reactivation of Kaposi’s sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein. Virology. 1998;252(2):304–12.PubMedGoogle Scholar
  182. 182.
    Xu Y, AuCoin DP, Huete AR, Cei SA, Hanson LJ, Pari GS. A Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 ORF50 deletion mutant is defective for reactivation of latent virus and DNA replication. J Virol. 2005;79(6):3479–87.PubMedCentralPubMedGoogle Scholar
  183. 183.
    Seaman WT, Ye D, Wang RX, Hale EE, Weisse M, Quinlivan EB. Gene expression from the ORF50/K8 region of Kaposi’s sarcoma-associated herpesvirus. Virology. 1999;263(2):436–49.PubMedGoogle Scholar
  184. 184.
    Zhu FX, Cusano T, Yuan Y. Identification of the immediate-early transcripts of Kaposi’s sarcoma-associated herpesvirus. J Virol. 1999;73(7):5556–67.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Sun R, Lin SF, Staskus K, Gradoville L, Grogan E, Haase A, et al. Kinetics of Kaposi’s sarcoma-associated herpesvirus gene expression. J Virol. 1999;73(3):2232–42.PubMedCentralPubMedGoogle Scholar
  186. 186.
    Lu F, Zhou J, Wiedmer A, Madden K, Yuan Y, Lieberman PM. Chromatin remodeling of the Kaposi’s sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency. J Virol. 2003;77(21):11425–35.PubMedCentralPubMedGoogle Scholar
  187. 187.
    Chen J, Ueda K, Sakakibara S, Okuno T, Parravicini C, Corbellino M, et al. Activation of latent Kaposi’s sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator. Proc Natl Acad Sci U S A. 2001;98(7):4119–24.PubMedCentralPubMedGoogle Scholar
  188. 188.
    Chen J, Ye F, Xie J, Kuhne K, Gao SJ. Genome-wide identification of binding sites for Kaposi’s sarcoma-associated herpesvirus lytic switch protein, RTA. Virology. 2009;386(2):290–302.PubMedCentralPubMedGoogle Scholar
  189. 189.
    Liang Y, Ganem D. RBP-J (CSL) is essential for activation of the K14/vGPCR promoter of Kaposi’s sarcoma-associated herpesvirus by the lytic switch protein RTA. J Virol. 2004;78(13):6818–26.PubMedCentralPubMedGoogle Scholar
  190. 190.
    Wang SE, Wu FY, Fujimuro M, Zong J, Hayward SD, Hayward GS. Role of CCAAT/enhancer-binding protein alpha (C/EBPalpha) in activation of the Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic-cycle replication-associated protein (RAP) promoter in cooperation with the KSHV replication and transcription activator (RTA) and RAP. J Virol. 2003;77(1):600–23.PubMedCentralPubMedGoogle Scholar
  191. 191.
    Deng H, Chu JT, Rettig MB, Martinez-Maza O, Sun R. Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up-regulates human interleukin-6 gene expression. Blood. 2002;100(5):1919–21.PubMedGoogle Scholar
  192. 192.
    Liang Y, Chang J, Lynch SJ, Lukac DM, Ganem D. The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jkappa (CSL), the target of the Notch signaling pathway. Genes Dev. 2002;16(15):1977–89.PubMedCentralPubMedGoogle Scholar
  193. 193.
    Deng H, Song MJ, Chu JT, Sun R. Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus). J Virol. 2002;76(16):8252–64.PubMedCentralPubMedGoogle Scholar
  194. 194.
    Lukac DM, Garibyan L, Kirshner JR, Palmeri D, Ganem D. DNA binding by Kaposi’s sarcoma-associated herpesvirus lytic switch protein is necessary for transcriptional activation of two viral delayed early promoters. J Virol. 2001;75(15):6786–99.PubMedCentralPubMedGoogle Scholar
  195. 195.
    Chen J, Ueda K, Sakakibara S, Okuno T, Yamanishi K. Transcriptional regulation of the Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor gene. J Virol. 2000;74(18):8623–34.PubMedCentralPubMedGoogle Scholar
  196. 196.
    Wang Y, Yuan Y. Essential role of RBP-Jkappa in activation of the K8 delayed-early promoter of Kaposi’s sarcoma-associated herpesvirus by ORF50/RTA. Virology. 2007;359(1):19–27.PubMedCentralPubMedGoogle Scholar
  197. 197.
    Wen HJ, Minhas V, Wood C. Identification and characterization of a new Kaposi’s sarcoma-associated herpesvirus replication and transcription activator (RTA)-responsive element involved in RTA-mediated transactivation. J Gen Virol. 2009;90(Pt 4):944–53.PubMedCentralPubMedGoogle Scholar
  198. 198.
    Jeong J, Papin J, Dittmer D. Differential regulation of the overlapping Kaposi’s sarcoma-associated herpesvirus vGCR (orf74) and LANA (orf73) promoters. J Virol. 2001;75(4):1798–807.PubMedCentralPubMedGoogle Scholar
  199. 199.
    Ziegelbauer J, Grundhoff A, Ganem D. Exploring the DNA binding interactions of the Kaposi’s sarcoma-associated herpesvirus lytic switch protein by selective amplification of bound sequences in vitro. J Virol. 2006;80(6):2958–67.PubMedCentralPubMedGoogle Scholar
  200. 200.
    Matsumura S, Fujita Y, Gomez E, Tanese N, Wilson AC. Activation of the Kaposi’s sarcoma-associated herpesvirus major latency locus by the lytic switch protein RTA (ORF50). J Virol. 2005;79(13):8493–505.PubMedCentralPubMedGoogle Scholar
  201. 201.
    Wang Y, Chong OT, Yuan Y. Differential regulation of K8 gene expression in immediate-early and delayed-early stages of Kaposi’s sarcoma-associated herpesvirus. Virology. 2004;325(1):149–63.PubMedGoogle Scholar
  202. 202.
    Wang SE, Wu FY, Yu Y, Hayward GS. CCAAT/enhancer-binding protein-alpha is induced during the early stages of Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic cycle reactivation and together with the KSHV replication and transcription activator (RTA) cooperatively stimulates the viral RTA, MTA, and PAN promoters. J Virol. 2003;77(17):9590–612.PubMedCentralPubMedGoogle Scholar
  203. 203.
    Sakakibara S, Ueda K, Chen J, Okuno T, Yamanishi K. Octamer-binding sequence is a key element for the autoregulation of Kaposi’s sarcoma-associated herpesvirus ORF50/Lyta gene expression. J Virol. 2001;75(15):6894–900.PubMedCentralPubMedGoogle Scholar
  204. 204.
    Gwack Y, Hwang S, Lim C, Won YS, Lee CH, Choe J. Kaposi’s Sarcoma-associated herpesvirus open reading frame 50 stimulates the transcriptional activity of STAT3. J Biol Chem. 2002;277(8):6438–42.PubMedGoogle Scholar
  205. 205.
    Gwack Y, Byun H, Hwang S, Lim C, Choe J. CREB-binding protein and histone deacetylase regulate the transcriptional activity of Kaposi’s sarcoma-associated herpesvirus open reading frame 50. J Virol. 2001;75(4):1909–17.PubMedCentralPubMedGoogle Scholar
  206. 206.
    Gwack Y, Baek HJ, Nakamura H, Lee SH, Meisterernst M, Roeder RG, et al. Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi’s sarcoma-associated herpesvirus RTA-mediated lytic reactivation. Mol Cell Biol. 2003;23(6):2055–67.PubMedCentralPubMedGoogle Scholar
  207. 207.
    Dalton-Griffin L, Wilson SJ, Kellam P. X-box binding protein 1 contributes to induction of the Kaposi’s sarcoma-associated herpesvirus lytic cycle under hypoxic conditions. J Virol. 2009;83(14):7202–9.PubMedCentralPubMedGoogle Scholar
  208. 208.
    AuCoin DP, Colletti KS, Cei SA, Papouskova I, Tarrant M, Pari GS. Amplification of the Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 lytic origin of DNA replication is dependent upon a cis-acting AT-rich region and an ORF50 response element and the trans-acting factors ORF50 (K-Rta) and K8 (K-bZIP). Virology. 2004;318(2):542–55.PubMedGoogle Scholar
  209. 209.
    Lin CL, Li H, Wang Y, Zhu FX, Kudchodkar S, Yuan Y. Kaposi’s sarcoma-associated herpesvirus lytic origin (ori-Lyt)-dependent DNA replication: identification of the ori-Lyt and association of K8 bZip protein with the origin. J Virol. 2003;77(10):5578–88.PubMedCentralPubMedGoogle Scholar
  210. 210.
    Wu FY, Ahn JH, Alcendor DJ, Jang WJ, Xiao J, Hayward SD, et al. Origin-independent assembly of Kaposi’s sarcoma-associated herpesvirus DNA replication compartments in transient cotransfection assays and association with the ORF-K8 protein and cellular PML. J Virol. 2001;75(3):1487–506.PubMedCentralPubMedGoogle Scholar
  211. 211.
    Lu M, Suen J, Frias C, Pfeiffer R, Tsai MH, Chuang E, et al. Dissection of the Kaposi’s sarcoma-associated herpesvirus gene expression program by using the viral DNA replication inhibitor cidofovir. J Virol. 2004;78(24):13637–52.PubMedCentralPubMedGoogle Scholar
  212. 212.
    Jenner RG, Alba MM, Boshoff C, Kellam P. Kaposi’s sarcoma-associated herpesvirus latent and lytic gene expression as revealed by DNA arrays. J Virol. 2001;75(2):891–902.PubMedCentralPubMedGoogle Scholar
  213. 213.
    Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.PubMedGoogle Scholar
  214. 214.
    Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe. 2011;9(5):363–75. Epub 2011/05/18.PubMedCentralPubMedGoogle Scholar
  215. 215.
    West J, Wicks M, Gregory SM, Chugh P, Jacobs SR, Zhang Z, Host KM, Dittmer DP, Damania B. An important role for mitochondrial antiviral signaling protein in the Kaposi’s sarcoma-associated herpesvirus life cycle. J Virol. 2014;88(10):5778–87. Epub 2014 Mar 12.PubMedGoogle Scholar
  216. 216.
    Zimring JC, Goodbourn S, Offermann MK. Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription. J Virol. 1998;72(1):701–7.PubMedCentralPubMedGoogle Scholar
  217. 217.
    Burysek L, Yeow WS, Lubyova B, Kellum M, Schafer SL, Huang YQ, et al. Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300. J Virol. 1999;73(9):7334–42.PubMedCentralPubMedGoogle Scholar
  218. 218.
    Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS. KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene. 1997;15(16):1979–85.PubMedGoogle Scholar
  219. 219.
    Lin R, Genin P, Mamane Y, Sgarbanti M, Battistini A, Harrington Jr WJ, et al. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene. 2001;20(7):800–11.PubMedGoogle Scholar
  220. 220.
    Li M, Damania B, Alvarez X, Ogryzko V, Ozato K, Jung JU. Inhibition of p300 histone acetyltransferase by viral interferon regulatory factor. Mol Cell Biol. 2000;20(21):8254–63.PubMedCentralPubMedGoogle Scholar
  221. 221.
    Fuld S, Cunningham C, Klucher K, Davison AJ, Blackbourn DJ. Inhibition of interferon signaling by the Kaposi’s sarcoma-associated herpesvirus full-length viral interferon regulatory factor 2 protein. J Virol. 2006;80(6):3092–7.PubMedCentralPubMedGoogle Scholar
  222. 222.
    Areste C, Mutocheluh M, Blackbourn DJ. Identification of caspase-mediated decay of interferon regulatory factor-3, exploited by a Kaposi sarcoma-associated herpesvirus immunoregulatory protein. J Biol Chem. 2009;284(35):23272–85.PubMedCentralPubMedGoogle Scholar
  223. 223.
    Lubyova B, Pitha PM. Characterization of a novel human herpesvirus 8-encoded protein, vIRF-3, that shows homology to viral and cellular interferon regulatory factors. J Virol. 2000;74(17):8194–201.PubMedCentralPubMedGoogle Scholar
  224. 224.
    Joo CH, Shin YC, Gack M, Wu L, Levy D, Jung JU. Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi’s sarcoma-associated herpesvirus viral IRF homolog vIRF3. J Virol. 2007;81(15):8282–92.PubMedCentralPubMedGoogle Scholar
  225. 225.
    Lubyova B, Kellum MJ, Frisancho AJ, Pitha PM. Kaposi’s sarcoma-associated herpesvirus-encoded vIRF-3 stimulates the transcriptional activity of cellular IRF-3 and IRF-7. J Biol Chem. 2004;279(9):7643–54.PubMedGoogle Scholar
  226. 226.
    Schmidt K, Wies E, Neipel F. Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor 3 inhibits gamma interferon and major histocompatibility complex class II expression. J Virol. 2011;85(9):4530–7. Epub 2011/02/25.PubMedCentralPubMedGoogle Scholar
  227. 227.
    Zhu FX, King SM, Smith EJ, Levy DE, Yuan Y. A Kaposi’s sarcoma-associated herpesviral protein inhibits virus-mediated induction of type I interferon by blocking IRF-7 phosphorylation and nuclear accumulation. Proc Natl Acad Sci U S A. 2002;99(8):5573–8.PubMedCentralPubMedGoogle Scholar
  228. 228.
    Yu Y, Wang SE, Hayward GS. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity. 2005;22(1):59–70.PubMedGoogle Scholar
  229. 229.
    Zhu FX, Li X, Zhou F, Gao SJ, Yuan Y. Functional characterization of Kaposi’s sarcoma-associated herpesvirus ORF45 by bacterial artificial chromosome-based mutagenesis. J Virol. 2006;80(24):12187–96.PubMedCentralPubMedGoogle Scholar
  230. 230.
    Zhu FX, Sathish N, Yuan Y. Antagonism of host antiviral responses by Kaposi’s sarcoma-associated herpesvirus tegument protein ORF45. PLoS One. 2010;5(5):e10573.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Coscoy L, Ganem D. Kaposi’s sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc Natl Acad Sci U S A. 2000;97(14):8051–6.PubMedCentralPubMedGoogle Scholar
  232. 232.
    Stevenson PG, Efstathiou S, Doherty PC, Lehner PJ. Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses. Proc Natl Acad Sci U S A. 2000;97(15):8455–60.PubMedCentralPubMedGoogle Scholar
  233. 233.
    Ishido S, Wang C, Lee BS, Cohen GB, Jung JU. Downregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. J Virol. 2000;74(11):5300–9.PubMedCentralPubMedGoogle Scholar
  234. 234.
    Bartee E, Mansouri M, Hovey Nerenberg BT, Gouveia K, Fruh K. Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins. J Virol. 2004;78(3):1109–20.PubMedCentralPubMedGoogle Scholar
  235. 235.
    Sanchez DJ, Gumperz JE, Ganem D. Regulation of CD1d expression and function by a herpesvirus infection. J Clin Invest. 2005;115(5):1369–78. Epub 2005/05/03.PubMedCentralPubMedGoogle Scholar
  236. 236.
    Coscoy L, Ganem D. A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation. J Clin Invest. 2001;107(12):1599–606.PubMedCentralPubMedGoogle Scholar
  237. 237.
    Ishido S, Choi JK, Lee BS, Wang C, DeMaria M, Johnson RP, et al. Inhibition of natural killer cell-mediated cytotoxicity by Kaposi’s sarcoma-associated herpesvirus K5 protein. Immunity. 2000;13(3):365–74.PubMedGoogle Scholar
  238. 238.
    Li Q, Means R, Lang S, Jung JU. Downregulation of gamma interferon receptor 1 by Kaposi’s sarcoma-associated herpesvirus K3 and K5. J Virol. 2007;81(5):2117–27.PubMedCentralPubMedGoogle Scholar
  239. 239.
    Thomas M, Boname JM, Field S, Nejentsev S, Salio M, Cerundolo V, et al. Down-regulation of NKG2D and NKp80 ligands by Kaposi’s sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2008;105(5):1656–61.PubMedCentralPubMedGoogle Scholar
  240. 240.
    Nicholas J, Ruvolo VR, Burns WH, Sandford G, Wan X, Ciufo D, et al. Kaposi’s sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. Nat Med. 1997;3(3):287–92.PubMedGoogle Scholar
  241. 241.
    Nicholas J. Human gammaherpesvirus cytokines and chemokine receptors. J Interferon Cytokine Res. 2005;25(7):373–83.PubMedGoogle Scholar
  242. 242.
    Stine JT, Wood C, Hill M, Epp A, Raport CJ, Schweickart VL, et al. KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood. 2000;95(4):1151–7.PubMedGoogle Scholar
  243. 243.
    Endres MJ, Garlisi CG, Xiao H, Shan L, Hedrick JA. The Kaposi’s sarcoma-related herpesvirus (KSHV)-encoded chemokine vMIP-I is a specific agonist for the CC chemokine receptor (CCR)8. J Exp Med. 1999;189(12):1993–8.PubMedCentralPubMedGoogle Scholar
  244. 244.
    Weber KS, Grone HJ, Rocken M, Klier C, Gu S, Wank R, et al. Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II. Eur J Immunol. 2001;31(8):2458–66.PubMedGoogle Scholar
  245. 245.
    Yamin R, Kaynan NS, Glasner A, Vitenshtein A, Tsukerman P, Bauman Y, et al. The viral KSHV chemokine vMIP-II inhibits the migration of Naive and activated human NK cells by antagonizing two distinct chemokine receptors. PLoS Pathog. 2013;9(8):e1003568. Epub 2013/08/24.PubMedCentralPubMedGoogle Scholar
  246. 246.
    Liu C, Okruzhnov Y, Li H, Nicholas J. Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects. J Virol. 2001;75(22):10933–40.PubMedCentralPubMedGoogle Scholar
  247. 247.
    Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, et al. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science. 1997;278(5336):290–4.PubMedGoogle Scholar
  248. 248.
    Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S, Reed JC, et al. Discovery of a viral NLR homolog that inhibits the inflammasome. Science. 2011;331(6015):330–4.PubMedCentralPubMedGoogle Scholar
  249. 249.
    Kanneganti TD. Central roles of NLRs and inflammasomes in viral infection. Nat Rev Immunol. 2010;10(10):688–98.PubMedCentralPubMedGoogle Scholar
  250. 250.
    Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290(5497):1768–71.PubMedGoogle Scholar
  251. 251.
    Chung YH, Means RE, Choi JK, Lee BS, Jung JU. Kaposi’s sarcoma-associated herpesvirus OX2 glycoprotein activates myeloid-lineage cells to induce inflammatory cytokine production. J Virol. 2002;76(10):4688–98.PubMedCentralPubMedGoogle Scholar
  252. 252.
    Foster-Cuevas M, Wright GJ, Puklavec MJ, Brown MH, Barclay AN. Human herpesvirus 8K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor. J Virol. 2004;78(14):7667–76.PubMedCentralPubMedGoogle Scholar
  253. 253.
    Rezaee SA, Gracie JA, McInnes IB, Blackbourn DJ. Inhibition of neutrophil function by the Kaposi’s sarcoma-associated herpesvirus vOX2 protein. AIDS. 2005;19(16):1907–10.PubMedGoogle Scholar
  254. 254.
    Salata C, Curtarello M, Calistri A, Sartori E, Sette P, de Bernard M, et al. vOX2 glycoprotein of human herpesvirus 8 modulates human primary macrophages activity. J Cell Physiol. 2009;219(3):698–706.PubMedGoogle Scholar
  255. 255.
    Misstear K, Chanas SA, Rezaee SA, Colman R, Quinn LL, Long HM, et al. Suppression of antigen-specific T cell responses by the Kaposi’s sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200. J Virol. 2012;86(11):6246–57. Epub 2012/04/12.PubMedCentralPubMedGoogle Scholar
  256. 256.
    Lee H, Guo J, Li M, Choi JK, DeMaria M, Rosenzweig M, et al. Identification of an immunoreceptor tyrosine-based activation motif of K1 transforming protein of Kaposi’s sarcoma-associated herpesvirus. Mol Cell Biol. 1998;18(9):5219–28.PubMedCentralPubMedGoogle Scholar
  257. 257.
    Lagunoff M, Majeti R, Weiss A, Ganem D. Deregulated signal transduction by the K1 gene product of Kaposi’s sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A. 1999;96(10):5704–9.PubMedCentralPubMedGoogle Scholar
  258. 258.
    Lee BS, Lee SH, Feng P, Chang H, Cho NH, Jung JU. Characterization of the Kaposi’s sarcoma-associated herpesvirus K1 signalosome. J Virol. 2005;79(19):12173–84.PubMedCentralPubMedGoogle Scholar
  259. 259.
    Tomlinson CC, Damania B. The K1 protein of Kaposi’s sarcoma-associated herpesvirus activates the Akt signaling pathway. J Virol. 2004;78(4):1918–27.PubMedCentralPubMedGoogle Scholar
  260. 260.
    Wen KW, Damania B. Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1. Oncogene. 2010;29(24):3532–44.PubMedCentralPubMedGoogle Scholar
  261. 261.
    Lee BS, Alvarez X, Ishido S, Lackner AA, Jung JU. Inhibition of intracellular transport of B cell antigen receptor complexes by Kaposi’s sarcoma-associated herpesvirus K1. J Exp Med. 2000;192(1):11–21.PubMedCentralPubMedGoogle Scholar
  262. 262.
    Lee H, Veazey R, Williams K, Li M, Guo J, Neipel F, et al. Deregulation of cell growth by the K1 gene of Kaposi’s sarcoma-associated herpesvirus. Nat Med. 1998;4(4):435–40.PubMedGoogle Scholar
  263. 263.
    Prakash O, Tang ZY, Peng X, Coleman R, Gill J, Farr G, et al. Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8K1 gene. J Natl Cancer Inst. 2002;94(12):926–35.PubMedGoogle Scholar
  264. 264.
    Prakash O, Swamy OR, Peng X, Tang ZY, Li L, Larson JE, et al. Activation of Src kinase Lyn by the Kaposi sarcoma-associated herpesvirus K1 protein: implications for lymphomagenesis. Blood. 2005;105(10):3987–94.PubMedCentralPubMedGoogle Scholar
  265. 265.
    Wang L, Wakisaka N, Tomlinson CC, DeWire SM, Krall S, Pagano JS, et al. The Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors. Cancer Res. 2004;64(8):2774–81.PubMedGoogle Scholar
  266. 266.
    Wang L, Dittmer DP, Tomlinson CC, Fakhari FD, Damania B. Immortalization of primary endothelial cells by the K1 protein of Kaposi’s sarcoma-associated herpesvirus. Cancer Res. 2006;66(7):3658–66.PubMedGoogle Scholar
  267. 267.
    Cesarman E, Nador RG, Bai F, Bohenzky RA, Russo JJ, Moore PS, et al. Kaposi’s sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi’s sarcoma and malignant lymphoma. J Virol. 1996;70(11):8218–23.PubMedCentralPubMedGoogle Scholar
  268. 268.
    Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis I. Chemokines activate Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture. J Clin Invest. 1998;102(8):1469–72.PubMedCentralPubMedGoogle Scholar
  269. 269.
    Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature. 1997;385(6614):347–50.PubMedGoogle Scholar
  270. 270.
    Smit MJ, Verzijl D, Casarosa P, Navis M, Timmerman H, Leurs R. Kaposi’s sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via G(i) and phospholipase C-dependent signaling pathways. J Virol. 2002;76(4):1744–52.PubMedCentralPubMedGoogle Scholar
  271. 271.
    Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA, et al. The Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res. 2000;60(17):4873–80.PubMedGoogle Scholar
  272. 272.
    Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, Sausville EA, et al. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell. 2006;10(2):133–43.PubMedGoogle Scholar
  273. 273.
    Sodhi A, Montaner S, Patel V, Gomez-Roman JJ, Li Y, Sausville EA, et al. Akt plays a central role in sarcomagenesis induced by Kaposi’s sarcoma herpesvirus-encoded G protein-coupled receptor. Proc Natl Acad Sci U S A. 2004;101(14):4821–6.PubMedCentralPubMedGoogle Scholar
  274. 274.
    Montaner S, Sodhi A, Pece S, Mesri EA, Gutkind JS. The Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B. Cancer Res. 2001;61(6):2641–8.PubMedGoogle Scholar
  275. 275.
    Cannon M, Philpott NJ, Cesarman E. The Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol. 2003;77(1):57–67.PubMedCentralPubMedGoogle Scholar
  276. 276.
    Schwarz M, Murphy PM. Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-kappa B and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol. 2001;167(1):505–13.PubMedGoogle Scholar
  277. 277.
    Martin D, Galisteo R, Ji Y, Montaner S, Gutkind JS. An NF-kappaB gene expression signature contributes to Kaposi’s sarcoma virus vGPCR-induced direct and paracrine neoplasia. Oncogene. 2008;27(13):1844–52.PubMedGoogle Scholar
  278. 278.
    Hanson J. Standardization of proximal femur BMD measurements. International Committee for Standards in Bone Measurement. Osteoporos Int. 1997;7(5):500–1.PubMedGoogle Scholar
  279. 279.
    Bais C, Van Geelen A, Eroles P, Mutlu A, Chiozzini C, Dias S, et al. Kaposi’s sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/KDR. Cancer Cell. 2003;3(2):131–43.PubMedGoogle Scholar
  280. 280.
    Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, et al. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 1998;391(6662):86–9.PubMedGoogle Scholar
  281. 281.
    Guo HG, Sadowska M, Reid W, Tschachler E, Hayward G, Reitz M. Kaposi’s sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J Virol. 2003;77(4):2631–9.PubMedCentralPubMedGoogle Scholar
  282. 282.
    Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y, et al. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi’s sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell. 2003;3(1):23–36.PubMedGoogle Scholar
  283. 283.
    Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, et al. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi’s sarcoma. J Exp Med. 2000;191(3):445–54.PubMedCentralPubMedGoogle Scholar
  284. 284.
    Cesarman E, Mesri EA, Gershengorn MC. Viral G protein-coupled receptor and Kaposi’s sarcoma: a model of paracrine neoplasia? J Exp Med. 2000;191(3):417–22.PubMedCentralPubMedGoogle Scholar
  285. 285.
    Wang Y, Lu X, Zhu L, Shen Y, Chengedza S, Feng H, et al. IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A. 2013;110(27):11139–44. Epub 2013/06/19.PubMedCentralPubMedGoogle Scholar
  286. 286.
    Montaner S, Sodhi A, Servitja JM, Ramsdell AK, Barac A, Sawai ET, et al. The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood. 2004;104(9):2903–11.PubMedGoogle Scholar
  287. 287.
    Glenn M, Rainbow L, Aurade F, Davison A, Schulz TF. Identification of a spliced gene from Kaposi’s sarcoma-associated herpesvirus encoding a protein with similarities to latent membrane proteins 1 and 2A of Epstein-Barr virus. J Virol. 1999;73(8):6953–63.PubMedCentralPubMedGoogle Scholar
  288. 288.
    Sharp TV, Wang HW, Koumi A, Hollyman D, Endo Y, Ye H, et al. K15 protein of Kaposi’s sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J Virol. 2002;76(2):802–16.PubMedCentralPubMedGoogle Scholar
  289. 289.
    Choi JK, Lee BS, Shim SN, Li M, Jung JU. Identification of the novel K15 gene at the rightmost end of the Kaposi’s sarcoma-associated herpesvirus genome. J Virol. 2000;74(1):436–46.PubMedCentralPubMedGoogle Scholar
  290. 290.
    Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF. Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi’s sarcoma-associated herpesvirus K15 membrane protein. J Virol. 2003;77(17):9346–58.PubMedCentralPubMedGoogle Scholar
  291. 291.
    Bala K, Bosco R, Gramolelli S, Haas DA, Kati S, Pietrek M, et al. Kaposi’s sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathog. 2012;8(9):e1002927. Epub 2012/10/03.PubMedCentralPubMedGoogle Scholar
  292. 292.
    Brinkmann MM, Pietrek M, Dittrich-Breiholz O, Kracht M, Schulz TF. Modulation of host gene expression by the K15 protein of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2007;81(1):42–58.PubMedCentralPubMedGoogle Scholar
  293. 293.
    Breen EC, Gage JR, Guo B, Magpantay L, Narazaki M, Kishimoto T, et al. Viral interleukin 6 stimulates human peripheral blood B cells that are unresponsive to human interleukin 6. Cell Immunol. 2001;212(2):118–25.PubMedGoogle Scholar
  294. 294.
    Li H, Wang H, Nicholas J. Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling. J Virol. 2001;75(7):3325–34.PubMedCentralPubMedGoogle Scholar
  295. 295.
    Li H, Nicholas J. Identification of amino acid residues of gp130 signal transducer and gp80 alpha receptor subunit that are involved in ligand binding and signaling by human herpesvirus 8-encoded interleukin-6. J Virol. 2002;76(11):5627–36.PubMedCentralPubMedGoogle Scholar
  296. 296.
    Hu F, Nicholas J. Signal transduction by human herpesvirus 8 viral interleukin-6 (vIL-6) is modulated by the nonsignaling gp80 subunit of the IL-6 receptor complex and is distinct from signaling induced by human IL-6. J Virol. 2006;80(21):10874–8.PubMedCentralPubMedGoogle Scholar
  297. 297.
    Jones KD, Aoki Y, Chang Y, Moore PS, Yarchoan R, Tosato G. Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi’s sarcoma herpesvirus-associated infected primary effusion lymphoma cells. Blood. 1999;94(8):2871–9.PubMedGoogle Scholar
  298. 298.
    Oksenhendler E, Boulanger E, Galicier L, Du MQ, Dupin N, Diss TC, et al. High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood. 2002;99(7):2331–6.PubMedGoogle Scholar
  299. 299.
    Parravicini C, Corbellino M, Paulli M, Magrini U, Lazzarino M, Moore PS, et al. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman’s disease. Am J Pathol. 1997;151(6):1517–22.PubMedGoogle Scholar
  300. 300.
    Chen D, Sandford G, Nicholas J. Intracellular signaling mechanisms and activities of human herpesvirus 8 interleukin-6. J Virol. 2009;83(2):722–33. Epub 2008/11/07.PubMedCentralPubMedGoogle Scholar
  301. 301.
    Meads MB, Medveczky PG. Kaposi's sarcoma-associated herpesvirus-encoded viral interleukin-6 is secreted and modified differently than human interleukin-6: evidence for a unique autocrine signaling mechanism. J Biol Chem. 2004;279(50):51793–803. Epub 2004/07/20.PubMedGoogle Scholar
  302. 302.
    Chen D, Choi YB, Sandford G, Nicholas J. Determinants of secretion and intracellular localization of human herpesvirus 8 interleukin-6. J Virol. 2009;83(13):6874–82. Epub 2009/04/24.PubMedCentralPubMedGoogle Scholar
  303. 303.
    Cousins E, Nicholas J. Role of human herpesvirus 8 interleukin-6-activated gp130 signal transducer in primary effusion lymphoma cell growth and viability. J Virol. 2013;87(19):10816–27. Epub 2013/08/02.PubMedCentralPubMedGoogle Scholar
  304. 304.
    Xiang Y, Ma N, Wang D, Zhang Y, Zhou J, Wu G, et al. MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine. Oncogene. 2014;33(3):378–86. Epub 2013/01/16.PubMedGoogle Scholar
  305. 305.
    Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996;271(2):736–41.PubMedGoogle Scholar
  306. 306.
    Aoki Y, Jaffe ES, Chang Y, Jones K, Teruya-Feldstein J, Moore PS, et al. Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6. Blood. 1999;93(12):4034–43.PubMedGoogle Scholar
  307. 307.
    Vart RJ, Nikitenko LL, Lagos D, Trotter MW, Cannon M, Bourboulia D, et al. Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res. 2007;67(9):4042–51.PubMedGoogle Scholar
  308. 308.
    Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, Rosean TR, Klapper W, Tosato G, et al. HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood. 2012;119(22):5173–81. Epub 2012/04/12.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Microbiology and Immunology, Lineberger Cancer Center, CB#7295University of North Carolina at Chapel HillChapel HillUSA

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