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Molecular Biology of KSHV in Relation to HIV/AIDS-Associated Oncogenesis

  • Meilan He
  • Fan Cheng
  • Suzane Ramos da Silva
  • Brandon Tan
  • Océane Sorel
  • Marion Gruffaz
  • Tingting Li
  • Shou-Jiang Gao
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 177)

Abstract

Discovered in 1994, Kaposi’s sarcoma-associated herpesvirus (KSHV) has been associated with four human malignancies including Kaposi’s sarcoma, primary effusion lymphoma, a subset of multicentric Castleman’s disease, and KSHV inflammatory cytokine syndrome. These malignancies mostly occur in immunocompromised patients including patients with acquired immunodeficiency syndrome and often cause significant mortality because of the lack of effective therapies. Significant progresses have been made to understand the molecular basis of KSHV infection and KSHV-induced oncogenesis in the last two decades. This chapter provides an update on the recent advancements focusing on the molecular events of KSHV primary infection, the mechanisms regulating KSHV life cycle, innate and adaptive immunity, mechanism of KSHV-induced tumorigenesis and inflammation, and metabolic reprogramming in KSHV infection and KSHV-transformed cells.

References

  1. 1.
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869CrossRefGoogle Scholar
  2. 2.
    Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332:1186–1191CrossRefGoogle Scholar
  3. 3.
    Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d’Agay MF, Clauvel JP, Raphael M, Degos L et al (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 86:1276–1280Google Scholar
  4. 4.
    Uldrick TS, Wang V, O’Mahony D, Aleman K, Wyvill KM, Marshall V, Steinberg SM, Pittaluga S, Maric I, Whitby D, Tosato G, Little RF, Yarchoan R (2010) 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 51:350–358CrossRefGoogle Scholar
  5. 5.
    Greene W, Kuhne K, Ye F, Chen J, Zhou F, Lei X, Gao SJ (2007) Molecular biology of KSHV in relation to AIDS-associated oncogenesis. Cancer Treat Res 133:69–127CrossRefGoogle Scholar
  6. 6.
    Robey RC, Bower M (2015) Facing up to the ongoing challenge of Kaposi’s sarcoma. Curr Opin Infect Dis 28:31–40CrossRefGoogle Scholar
  7. 7.
    Okada S, Goto H, Yotsumoto M (2014) Current status of treatment for primary effusion lymphoma. Intractable Rare Dis Res 3:65–74CrossRefGoogle Scholar
  8. 8.
    Carbone A, De Paoli P, Gloghini A, Vaccher E (2015) KSHV-associated multicentric Castleman disease: a tangle of different entities requiring multitarget treatment strategies. Int J Cancer 137:251–261CrossRefGoogle Scholar
  9. 9.
    Polizzotto MN, Uldrick TS, Hu D, Yarchoan R (2012) Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome. Front Microbiol 3:73CrossRefGoogle Scholar
  10. 10.
    Tso FY, Sawyer A, Kwon EH, Mudenda V, Langford D, Zhou Y, West J, Wood C (2016) Kaposi’s sarcoma-associated herpesvirus infection of neurons in HIV positive patients. J Infect DisGoogle Scholar
  11. 11.
    Bechtel JT, Liang Y, Hvidding J, Ganem D (2003) Host range of Kaposi’s sarcoma-associated herpesvirus in cultured cells. J Virol 77:6474–6481CrossRefGoogle Scholar
  12. 12.
    Hahn AS, Kaufmann JK, Wies E, Naschberger E, Panteleev-Ivlev J, Schmidt K, Holzer A, Schmidt M, Chen J, Konig S, Ensser A, Myoung J, Brockmeyer NH, Sturzl M, Fleckenstein B, Neipel F (2012) The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus. Nat Med 18:961–966CrossRefGoogle Scholar
  13. 13.
    Akula SM, Pramod NP, Wang FZ, Chandran B (2002) Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108:407–419CrossRefGoogle Scholar
  14. 14.
    Jones T, Ye F, Bedolla R, Huang Y, Meng J, Qian L, Pan H, Zhou F, Moody R, Wagner B, Arar M, Gao SJ (2012) Direct and efficient cellular transformation of primary rat mesenchymal precursor cells by KSHV. J Clin Invest 122:1076–1081CrossRefGoogle Scholar
  15. 15.
    Foglieni C, Scabini S, Belloni D, Broccolo F, Lusso P, Malnati MS, Ferrero E (2005) Productive infection of HUVEC by HHV-8 is associated with changes compatible with angiogenic transformations. Eur J Histochem 49:273–284CrossRefGoogle Scholar
  16. 16.
    Gao SJ, Deng JH, Zhou FC (2003) Productive lytic replication of a recombinant Kaposi’s sarcoma-associated herpesvirus in efficient primary infection of primary human endothelial cells. J Virol 77:9738–9749CrossRefGoogle Scholar
  17. 17.
    Kumar B, Chandran B (2016) KSHV entry and trafficking in target cells-hijacking of cell signal pathways, actin and membrane dynamics. Viruses 8Google Scholar
  18. 18.
    Zhang W, Gao SJ (2012) Exploitation of cellular cytoskeletons and signaling pathways for cell entry by Kaposi’s sarcoma-associated herpesvirus and the closely related rhesus rhadinovirus. Pathogens 1:102–127CrossRefGoogle Scholar
  19. 19.
    Akula SM, Wang FZ, Vieira J, Chandran B (2001) Human herpesvirus 8 interaction with target cells involves heparan sulfate. Virology 282:245–255CrossRefGoogle Scholar
  20. 20.
    Hahn A, Birkmann A, Wies E, Dorer D, Mahr K, Sturzl M, Titgemeyer F, Neipel F (2009) Kaposi’s sarcoma-associated herpesvirus gH/gL: glycoprotein export and interaction with cellular receptors. J Virol 83:396–407CrossRefGoogle Scholar
  21. 21.
    Wang FZ, Akula SM, Pramod NP, Zeng L, Chandran B (2001) Human herpesvirus 8 envelope glycoprotein K8.1A interaction with the target cells involves heparan sulfate. J Virol 75:7517–7527CrossRefGoogle Scholar
  22. 22.
    Birkmann A, Mahr K, Ensser A, Yaguboglu S, Titgemeyer F, Fleckenstein B, Neipel F (2001) Cell surface heparan sulfate is a receptor for human herpesvirus 8 and interacts with envelope glycoprotein K8.1. J Virol 75:11583–11593CrossRefGoogle Scholar
  23. 23.
    Kerur N, Veettil MV, Sharma-Walia N, Sadagopan S, Bottero V, Paul AG, Chandran B (2010) Characterization of entry and infection of monocytic THP-1 cells by Kaposi’s sarcoma associated herpesvirus (KSHV): role of heparan sulfate, DC-SIGN, integrins and signaling. Virology 406:103–116CrossRefGoogle Scholar
  24. 24.
    Veettil MV, Sadagopan S, Sharma-Walia N, Wang FZ, Raghu H, Varga L, Chandran B (2008) Kaposi’s sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection. J Virol 82:12126–12144CrossRefGoogle Scholar
  25. 25.
    Garrigues HJ, DeMaster LK, Rubinchikova YE, Rose TM (2014) KSHV attachment and entry are dependent on alphaVbeta3 integrin localized to specific cell surface microdomains and do not correlate with the presence of heparan sulfate. Virology 464–465:118–133CrossRefGoogle Scholar
  26. 26.
    Rappocciolo G, Hensler HR, Jais M, Reinhart TA, Pegu A, Jenkins FJ, Rinaldo CR (2008) Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN. J Virol 82:4793–4806CrossRefGoogle Scholar
  27. 27.
    Rappocciolo G, Jenkins FJ, Hensler HR, Piazza P, Jais M, Borowski L, Watkins SC, Rinaldo CR Jr (2006) DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. J Immunol 176:1741–1749CrossRefGoogle Scholar
  28. 28.
    Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, Maher P (2013) The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal 18:522–555CrossRefGoogle Scholar
  29. 29.
    Kaleeba JA, Berger EA (2006) Kaposi’s sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT. Science 311:1921–1924CrossRefGoogle Scholar
  30. 30.
    Hahn AS, Desrosiers RC (2014) Binding of the Kaposi’s sarcoma-associated herpesvirus to the ephrin binding surface of the EphA2 receptor and its inhibition by a small molecule. J Virol 88:8724–8734CrossRefGoogle Scholar
  31. 31.
    Chakraborty S, Veettil MV, Bottero V, Chandran B (2012) Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc Natl Acad Sci U S A 109:E1163–72CrossRefGoogle Scholar
  32. 32.
    Dutta D, Chakraborty S, Bandyopadhyay C, Valiya Veettil M, Ansari MA, Singh VV, Chandran B (2013) EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog 9:e1003510CrossRefGoogle Scholar
  33. 33.
    Akula SM, Naranatt PP, Walia NS, Wang FZ, Fegley B, Chandran B (2003) Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) infection of human fibroblast cells occurs through endocytosis. J Virol 77:7978–7990CrossRefGoogle Scholar
  34. 34.
    Greene W, Gao SJ (2009) Actin dynamics regulate multiple endosomal steps during Kaposi’s sarcoma-associated herpesvirus entry and trafficking in endothelial cells. PLoS Pathog 5:e1000512CrossRefGoogle Scholar
  35. 35.
    Inoue N, Winter J, Lal RB, Offermann MK, Koyano S (2003) Characterization of entry mechanisms of human herpesvirus 8 by using an Rta-dependent reporter cell line. J Virol 77:8147–8152CrossRefGoogle Scholar
  36. 36.
    Raghu H, Sharma-Walia N, Veettil MV, Sadagopan S, Chandran B (2009) 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 83:4895–4911CrossRefGoogle Scholar
  37. 37.
    Valiya Veettil M, Sadagopan S, Kerur N, Chakraborty S, Chandran B (2010) Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi’s sarcoma-associated herpesvirus. PLoS Pathog 6:e1001238CrossRefGoogle Scholar
  38. 38.
    Veettil MV, Kumar B, Ansari MA, Dutta D, Iqbal J, Gjyshi O, Bottero V, Chandran B (2016) ESCRT-0 component Hrs Promotes Macropinocytosis of Kaposi’s Sarcoma-associated herpesvirus in human dermal microvascular endothelial cells. J Virol 90:3860–3872CrossRefGoogle Scholar
  39. 39.
    Kumar B, Dutta D, Iqbal J, Ansari MA, Roy A, Chikoti L, Pisano G, Veettil MV, Chandran B (2016) ESCRT-I protein Tsg101 plays a role in the post-macropinocytic trafficking and infection of endothelial cells by Kaposi’s sarcoma-associated herpesvirus. PLoS Pathog 12:e1005960CrossRefGoogle Scholar
  40. 40.
    Naranatt PP, Krishnan HH, Smith MS, Chandran B (2005) 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 79:1191–1206CrossRefGoogle Scholar
  41. 41.
    Sharma-Walia N, Naranatt PP, Krishnan HH, Zeng L, Chandran B (2004) 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 78:4207–4223CrossRefGoogle Scholar
  42. 42.
    Krishnan HH, Sharma-Walia N, Streblow DN, Naranatt PP, Chandran B (2006) Focal adhesion kinase is critical for entry of Kaposi’s sarcoma-associated herpesvirus into target cells. J Virol 80:1167–1180CrossRefGoogle Scholar
  43. 43.
    Naik MU, Naik UP (2003) Calcium-and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen. Blood 102:3629–3636CrossRefGoogle Scholar
  44. 44.
    Naik MU, Naik UP (2011) Contra-regulation of calcium- and integrin-binding protein 1-induced cell migration on fibronectin by PAK1 and MAP kinase signaling. J Cell Biochem 112:3289–3299CrossRefGoogle Scholar
  45. 45.
    Bandyopadhyay C, Valiya-Veettil M, Dutta D, Chakraborty S, Chandran B (2014) CIB1 synergizes with EphrinA2 to regulate Kaposi’s sarcoma-associated herpesvirus macropinocytic entry in human microvascular dermal endothelial cells. PLoS Pathog 10:e1003941CrossRefGoogle Scholar
  46. 46.
    Chakraborty S, ValiyaVeettil M, Sadagopan S, Paudel N, Chandran B (2011) c-Cbl-mediated selective virus-receptor translocations into lipid rafts regulate productive Kaposi’s sarcoma-associated herpesvirus infection in endothelial cells. J Virol 85:12410–12430CrossRefGoogle Scholar
  47. 47.
    Greene W, Zhang W, He M, Witt C, Ye F, Gao SJ (2012) The ubiquitin/proteasome system mediates entry and endosomal trafficking of Kaposi’s sarcoma-associated herpesvirus in endothelial cells. PLoS Pathog 8:e1002703CrossRefGoogle Scholar
  48. 48.
    Bottero V, Chakraborty S, Chandran B (2013) Reactive oxygen species are induced by Kaposi’s sarcoma-associated herpesvirus early during primary infection of endothelial cells to promote virus entry. J Virol 87:1733–1749CrossRefGoogle Scholar
  49. 49.
    Pan H, Xie J, Ye F, Gao SJ (2006) 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 80:5371–5382CrossRefGoogle Scholar
  50. 50.
    Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B (2005) 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 79:10308–10329CrossRefGoogle Scholar
  51. 51.
    Xie J, Pan H, Yoo S, Gao SJ (2005) 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 79:15027–15037CrossRefGoogle Scholar
  52. 52.
    Qin Z, Dai L, Defee M, Findlay VJ, Watson DK, Toole BP, Cameron J, Peruzzi F, Kirkwood K, Parsons C (2013) Kaposi’s sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection. J Virol 87:621–635CrossRefGoogle Scholar
  53. 53.
    Cheng F, Sawant TV, Lan K, Lu C, Jung JU, Gao SJ (2015) Screening of the human kinome identifies MSK1/2-CREB1 as an essential pathway mediating Kaposi’s sarcoma-associated herpesvirus lytic replication during primary infection. J Virol 89:9262–9280CrossRefGoogle Scholar
  54. 54.
    Cheng F, He M, Jung JU, Lu C, Gao SJ (2016) Suppression of Kaposi’s sarcoma-associated herpesvirus infection and replication by 5’-AMP-activated protein kinase. J Virol 90:6515–6525CrossRefGoogle Scholar
  55. 55.
    Sadagopan S, Sharma-Walia N, Veettil MV, Raghu H, Sivakumar R, Bottero V, Chandran B (2007) 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 81:3949–3968CrossRefGoogle Scholar
  56. 56.
    Gjyshi O, Bottero V, Veettil MV, Dutta S, Singh VV, Chikoti L, Chandran B (2014) Kaposi’s sarcoma-associated herpesvirus induces Nrf2 during de novo infection of endothelial cells to create a microenvironment conducive to infection. PLoS Pathog 10:e1004460CrossRefGoogle Scholar
  57. 57.
    Yoo SM, Zhou FC, Ye FC, Pan HY, Gao SJ (2005) 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 343:47–64CrossRefGoogle Scholar
  58. 58.
    Krishnan HH, Naranatt PP, Smith MS, Zeng L, Bloomer C, Chandran B (2004) 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 78:3601–3620CrossRefGoogle Scholar
  59. 59.
    Purushothaman P, Thakker S, Verma SC (2015) Transcriptome analysis of Kaposi’s sarcoma-associated herpesvirus during de novo primary infection of human B and endothelial cells. J Virol 89:3093–3111CrossRefGoogle Scholar
  60. 60.
    Toth Z, Brulois K, Lee HR, Izumiya Y, Tepper C, Kung HJ, Jung JU (2013) Biphasic euchromatin-to-heterochromatin transition on the KSHV genome following de novo infection. PLoS Pathog 9:e1003813CrossRefGoogle Scholar
  61. 61.
    Gunther T, Grundhoff A (2010) The epigenetic landscape of latent Kaposi’s sarcoma-associated herpesvirus genomes. PLoS Pathog 6:e1000935CrossRefGoogle Scholar
  62. 62.
    Toth Z, Maglinte DT, Lee SH, Lee HR, Wong LY, Brulois KF, Lee S, Buckley JD, Laird PW, Marquez VE, Jung JU (2010) Epigenetic analysis of KSHV latent and lytic genomes. PLoS Pathog 6:e1001013CrossRefGoogle Scholar
  63. 63.
    Toth Z, Papp B, Brulois K, Choi YJ, Gao SJ, Jung JU (2016) LANA-mediated recruitment of host polycomb repressive complexes onto the KSHV genome during de novo infection. PLoS Pathog 12:e1005878CrossRefGoogle Scholar
  64. 64.
    Singh VV, Dutta D, Ansari MA, Dutta S, Chandran B (2014) Kaposi’s sarcoma-associated herpesvirus induces the ATM and H2AX DNA damage response early during de novo infection of primary endothelial cells, which play roles in latency establishment. J Virol 88:2821–2834CrossRefGoogle Scholar
  65. 65.
    Ye F, Lei X, Gao SJ (2011) Mechanisms of Kaposi’s sarcoma-associated herpesvirus latency and reactivation. Adv VirolGoogle Scholar
  66. 66.
    Dittmer D, Lagunoff M, Renne R, Staskus K, Haase A, Ganem D (1998) A cluster of latently expressed genes in Kaposi’s sarcoma-associated herpesvirus. J Virol 72:8309–8315Google Scholar
  67. 67.
    Pearce M, Matsumura S, Wilson AC (2005) Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi’s sarcoma-associated herpesvirus originate from a common promoter. J Virol 79:14457–14464CrossRefGoogle Scholar
  68. 68.
    Sarid R, Wiezorek JS, Moore PS, Chang Y (1999) Characterization and cell cycle regulation of the major Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) latent genes and their promoter. J Virol 73:1438–1446Google Scholar
  69. 69.
    Staudt MR, Dittmer DP (2006) Promoter switching allows simultaneous transcription of LANA and K14/vGPCR of Kaposi’s sarcoma-associated herpesvirus. Virology 350:192–205CrossRefGoogle Scholar
  70. 70.
    Samols MA, Hu J, Skalsky RL, Renne R (2005) Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi’s sarcoma-associated herpesvirus. J Virol 79:9301–9305CrossRefGoogle Scholar
  71. 71.
    Cunningham C, Barnard S, Blackbourn DJ, Davison AJ (2003) Transcription mapping of human herpesvirus 8 genes encoding viral interferon regulatory factors. J Gen Virol 84:1471–1483CrossRefGoogle Scholar
  72. 72.
    Gao S-J, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, Saah A, Phair J, Detels R, Parry P, Chang Y, Moore PS (1996) Seroconversion to antibodies against Kaposi’s sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi’s sarcoma. N Engl J Med 335:233–241CrossRefGoogle Scholar
  73. 73.
    Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, Ziegler J, Newton R, Rinaldo CR, Saah A, Phair J, Detels R, Chang Y, Moore PS (1996) KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi’s sarcoma. Nat Med 2:925–928CrossRefGoogle Scholar
  74. 74.
    Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D (1996) The seroepidemiology of human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med 2:918–924CrossRefGoogle Scholar
  75. 75.
    Zhang YJ, Deng JH, Rabkin C, Gao SJ (2000) Hot-spot variations of Kaposi’s sarcoma-associated herpesvirus latent nuclear antigen and application in genotyping by PCR-RFLP. J Gen Virol 81:2049–2058CrossRefGoogle Scholar
  76. 76.
    Kwun HJ, da Silva SR, Qin H, Ferris RL, Tan R, Chang Y, Moore PS (2011) The central repeat domain 1 of Kaposi’s sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) prevents cis MHC class I peptide presentation. Virology 412:357–365CrossRefGoogle Scholar
  77. 77.
    Kwun HJ, da Silva SR, Shah IM, Blake N, Moore PS, Chang Y (2007) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mimics Epstein-Barr virus EBNA1 immune evasion through central repeat domain effects on protein processing. J Virol 81:8225–8235CrossRefGoogle Scholar
  78. 78.
    Canham M, Talbot SJ (2004) A naturally occurring C-terminal truncated isoform of the latent nuclear antigen of Kaposi’s sarcoma-associated herpesvirus does not associate with viral episomal DNA. J Gen Virol 85:1363–1369CrossRefGoogle Scholar
  79. 79.
    Kwun HJ, Toptan T, Ramos da Silva S, Atkins JF, Moore PS, Chang Y (2014) Human DNA tumor viruses generate alternative reading frame proteins through repeat sequence recoding. Proc Natl Acad Sci U S A 111:E4342–9CrossRefGoogle Scholar
  80. 80.
    Ballestas ME, Chatis PA, Kaye KM (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284:641–644CrossRefGoogle Scholar
  81. 81.
    Ueda K, Sakakibara S, Ohsaki E, Yada K (2006) Lack of a mechanism for faithful partition and maintenance of the KSHV genome. Virus Res 122:85–94CrossRefGoogle Scholar
  82. 82.
    Gao SJ, Zhang YJ, Deng JH, Rabkin CS, Flore O, Jenson HB (1999) Molecular polymorphism of Kaposi’s sarcoma-associated herpesvirus (Human herpesvirus 8) latent nuclear antigen: evidence for a large repertoire of viral genotypes and dual infection with different viral genotypes. J Infect Dis 180:1466–1476CrossRefGoogle Scholar
  83. 83.
    Ye FC, Zhou FC, Yoo SM, Xie JP, Browning PJ, Gao SJ (2004) Disruption of Kaposi’s sarcoma-associated herpesvirus latent nuclear antigen leads to abortive episome persistence. J Virol 78:11121–11129CrossRefGoogle Scholar
  84. 84.
    Cherezova L, Burnside KL, Rose TM (2011) Conservation of complex nuclear localization signals utilizing classical and non-classical nuclear import pathways in LANA homologs of KSHV and RFHV. PLoS ONE 6:e18920CrossRefGoogle Scholar
  85. 85.
    Ballestas ME, Kaye KM (2001) 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 75:3250–3258CrossRefGoogle Scholar
  86. 86.
    Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Luger K, Kaye KM (2006) Kaposi’s sarcoma-associated herpesvirus LANA hitches a ride on the chromosome. Cell Cycle 5:1048–1052CrossRefGoogle Scholar
  87. 87.
    Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Joukov V, Walter JC, Luger K, Kaye KM (2006) The nucleosomal surface as a docking station for Kaposi’s sarcoma herpesvirus LANA. Science 311:856–861CrossRefGoogle Scholar
  88. 88.
    Kelley-Clarke B, De Leon-Vazquez E, Slain K, Barbera AJ, Kaye KM (2009) Role of Kaposi’s sarcoma-associated herpesvirus C-terminal LANA chromosome binding in episome persistence. J Virol 83:4326–4337CrossRefGoogle Scholar
  89. 89.
    Lim C, Lee D, Seo T, Choi C, Choe J (2003) Latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus functionally interacts with heterochromatin protein 1. J Biol Chem 278:7397–7405CrossRefGoogle Scholar
  90. 90.
    Pan HY, Zhang YJ, Wang XP, Deng JH, Zhou FC, Gao SJ (2003) Identification of a novel cellular transcriptional repressor interacting with the latent nuclear antigen of Kaposi’s sarcoma-associated herpesvirus. J Virol 77:9758–9768CrossRefGoogle Scholar
  91. 91.
    Matsumura S, Persson LM, Wong L, Wilson AC (2010) The latency-associated nuclear antigen interacts with MeCP2 and nucleosomes through separate domains. J Virol 84:2318–2330CrossRefGoogle Scholar
  92. 92.
    Ottinger M, Christalla T, Nathan K, Brinkmann MM, Viejo-Borbolla A, Schulz TF (2006) Kaposi’s sarcoma-associated herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3-induced G1 cell cycle arrest. J Virol 80:10772–10786CrossRefGoogle Scholar
  93. 93.
    Xiao B, Verma SC, Cai Q, Kaul R, Lu J, Saha A, Robertson ES (2010) Bub1 and CENP-F can contribute to Kaposi’s sarcoma-associated herpesvirus genome persistence by targeting LANA to kinetochores. J Virol 84:9718–9732CrossRefGoogle Scholar
  94. 94.
    Si H, Verma SC, Lampson MA, Cai Q, Robertson ES (2008) Kaposi’s sarcoma-associated herpesvirus-encoded LANA can interact with the nuclear mitotic apparatus protein to regulate genome maintenance and segregation. J Virol 82:6734–6746CrossRefGoogle Scholar
  95. 95.
    Verma SC, Choudhuri T, Kaul R, Robertson ES (2006) Latency-associated nuclear antigen (LANA) of Kaposi’s sarcoma-associated herpesvirus interacts with origin recognition complexes at the LANA binding sequence within the terminal repeats. J Virol 80:2243–2256CrossRefGoogle Scholar
  96. 96.
    Lan K, Kuppers DA, Verma SC, Robertson ES (2004) Kaposi’s sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency. J Virol 78:6585–6594CrossRefGoogle Scholar
  97. 97.
    Li Q, Zhou F, Ye F, Gao SJ (2008) Genetic disruption of KSHV major latent nuclear antigen LANA enhances viral lytic transcriptional program. Virology 379:234–244CrossRefGoogle Scholar
  98. 98.
    Li Q, He M, Zhou F, Ye F, Gao SJ (2014) Activation of Kaposi’s sarcoma-associated herpesvirus (KSHV) by inhibitors of class III histone deacetylases: identification of sirtuin 1 as a regulator of the KSHV life cycle. J Virol 88:6355–6367CrossRefGoogle Scholar
  99. 99.
    He M, Gao SJ (2014) A novel role of SIRT1 in gammaherpesvirus latency and replication. Cell Cycle 13:3328–3330CrossRefGoogle Scholar
  100. 100.
    Stedman W, Deng Z, Lu F, Lieberman PM (2004) ORC, MCM, and histone hyperacetylation at the Kaposi’s sarcoma-associated herpesvirus latent replication origin. J Virol 78:12566–12575CrossRefGoogle Scholar
  101. 101.
    Lu F, Zhou J, Wiedmer A, Madden K, Yuan Y, Lieberman PM (2003) Chromatin remodeling of the Kaposi’s sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency. J Virol 77:11425–11435CrossRefGoogle Scholar
  102. 102.
    Chen J, Ueda K, Sakakibara S, Okuno T, Parravicini C, Corbellino M, Yamanishi K (2001) Activation of latent Kaposi’s sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator. Proc Natl Acad Sci U S A 98:4119–4124CrossRefGoogle Scholar
  103. 103.
    Ohsaki E, Ueda K, Sakakibara S, Do E, Yada K, Yamanishi K (2004) Poly(ADP-ribose) polymerase 1 binds to Kaposi’s sarcoma-associated herpesvirus (KSHV) terminal repeat sequence and modulates KSHV replication in latency. J Virol 78:9936–9946CrossRefGoogle Scholar
  104. 104.
    Hyun TS, Subramanian C, Cotter MA 2nd, Thomas RA, Robertson ES (2001) Latency-associated nuclear antigen encoded by Kaposi’s sarcoma-associated herpesvirus interacts with Tat and activates the long terminal repeat of human immunodeficiency virus type 1 in human cells. J Virol 75:8761–8771CrossRefGoogle Scholar
  105. 105.
    Garber AC, Shu MA, Hu J, Renne R (2001) DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus. J Virol 75:7882–7892CrossRefGoogle Scholar
  106. 106.
    Stedman W, Kang H, Lin S, Kissil JL, Bartolomei MS, Lieberman PM (2008) Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators. EMBO J 27:654–666CrossRefGoogle Scholar
  107. 107.
    Kang H, Lieberman PM (2009) Cell cycle control of Kaposi’s sarcoma-associated herpesvirus latency transcription by CTCF-cohesin interactions. J Virol 83:6199–6210CrossRefGoogle Scholar
  108. 108.
    Kang H, Wiedmer A, Yuan Y, Robertson E, Lieberman PM (2011) Coordination of KSHV latent and lytic gene control by CTCF-cohesin mediated chromosome conformation. PLoS Pathog 7:e1002140CrossRefGoogle Scholar
  109. 109.
    Chen HS, Wikramasinghe P, Showe L, Lieberman PM (2012) Cohesins repress Kaposi’s sarcoma-associated herpesvirus immediate early gene transcription during latency. J Virol 86:9454–9464CrossRefGoogle Scholar
  110. 110.
    Kang H, Cho H, Sung GH, Lieberman PM (2013) CTCF regulates Kaposi’s sarcoma-associated herpesvirus latency transcription by nucleosome displacement and RNA polymerase programming. J Virol 87:1789–1799CrossRefGoogle Scholar
  111. 111.
    Ye FC, Zhou FC, Xie JP, Kang T, Greene W, Kuhne K, Lei XF, Li QH, Gao SJ (2008) Kaposi’s sarcoma-associated herpesvirus latent gene vFLIP inhibits viral lytic replication through NF-kappaB-mediated suppression of the AP-1 pathway: a novel mechanism of virus control of latency. J Virol 82:4235–4249CrossRefGoogle Scholar
  112. 112.
    Lei X, Bai Z, Ye F, Xie J, Kim CG, Huang Y, Gao SJ (2010) Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol 12:193–199CrossRefGoogle Scholar
  113. 113.
    Bellare P, Ganem D (2009) Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation. Cell Host Microbe 6:570–575CrossRefGoogle Scholar
  114. 114.
    Lu CC, Li Z, Chu CY, Feng J, Sun R, Rana TM (2010) MicroRNAs encoded by Kaposi’s sarcoma-associated herpesvirus regulate viral life cycle. EMBO Rep 11:784–790CrossRefGoogle Scholar
  115. 115.
    Lu F, Stedman W, Yousef M, Renne R, Lieberman PM (2010) Epigenetic regulation of Kaposi’s sarcoma-associated herpesvirus latency by virus-encoded microRNAs that target Rta and the cellular Rbl2-DNMT pathway. J Virol 84:2697–2706CrossRefGoogle Scholar
  116. 116.
    Liang D, Gao Y, Lin X, He Z, Zhao Q, Deng Q, Lan K (2011) A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKepsilon. Cell Res 21:793–806CrossRefGoogle Scholar
  117. 117.
    Lin X, Liang D, He Z, Deng Q, Robertson ES, Lan K (2011) miR-K12-7-5p encoded by Kaposi’s sarcoma-associated herpesvirus stabilizes the latent state by targeting viral ORF50/RTA. PLoS ONE 6:e16224CrossRefGoogle Scholar
  118. 118.
    Bai Z, Huang Y, Li W, Zhu Y, Jung JU, Lu C, Gao SJ (2014) Genomewide mapping and screening of Kaposi’s sarcoma-associated herpesvirus (KSHV) 3′ untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs. J Virol 88:377–392CrossRefGoogle Scholar
  119. 119.
    Arias C, Weisburd B, Stern-Ginossar N, Mercier A, Madrid AS, Bellare P, Holdorf M, Weissman JS, Ganem D (2014) KSHV 2.0: a comprehensive annotation of the Kaposi’s sarcoma-associated herpesvirus genome using next-generation sequencing reveals novel genomic and functional features. PLoS Pathog 10:e1003847CrossRefGoogle Scholar
  120. 120.
    Lukac DM, Renne R, Kirshner JR, Ganem D (1998) 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 252:304–312CrossRefGoogle Scholar
  121. 121.
    Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G (1998) A viral gene that activates lytic cycle expression of Kaposi’s sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 95:10866–10871CrossRefGoogle Scholar
  122. 122.
    Gradoville L, Gerlach J, Grogan E, Shedd D, Nikiforow S, Metroka C, Miller G (2000) 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 74:6207–6212CrossRefGoogle Scholar
  123. 123.
    Song MJ, Brown HJ, Wu TT, Sun R (2001) Transcription activation of polyadenylated nuclear rna by rta in human herpesvirus 8/Kaposi’s sarcoma-associated herpesvirus. J Virol 75:3129–3140CrossRefGoogle Scholar
  124. 124.
    Bu W, Palmeri D, Krishnan R, Marin R, Aris VM, Soteropoulos P, Lukac DM (2008) Identification of direct transcriptional targets of the Kaposi’s sarcoma-associated herpesvirus Rta lytic switch protein by conditional nuclear localization. J Virol 82:10709–10723CrossRefGoogle Scholar
  125. 125.
    Chen J, Ye F, Xie J, Kuhne K, Gao SJ (2009) Genome-wide identification of binding sites for Kaposi’s sarcoma-associated herpesvirus lytic switch protein, RTA. Virology 386:290–302CrossRefGoogle Scholar
  126. 126.
    Ziegelbauer J, Grundhoff A, Ganem D (2006) 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 80:2958–2967CrossRefGoogle Scholar
  127. 127.
    Ye J, Shedd D, Miller G (2005) An Sp1 response element in the Kaposi’s sarcoma-associated herpesvirus open reading frame 50 promoter mediates lytic cycle induction by butyrate. J Virol 79:1397–1408CrossRefGoogle Scholar
  128. 128.
    Carroll KD, Khadim F, Spadavecchia S, Palmeri D, Lukac DM (2007) Direct interactions of Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 ORF50/Rta protein with the cellular protein octamer-1 and DNA are critical for specifying transactivation of a delayed-early promoter and stimulating viral reactivation. J Virol 81:8451–8467CrossRefGoogle Scholar
  129. 129.
    Wilson SJ, Tsao EH, Webb BL, Ye H, Dalton-Griffin L, Tsantoulas C, Gale CV, Du MQ, Whitehouse A, Kellam P (2007) X box binding protein XBP-1 s transactivates the Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency. J Virol 81:13578–13586CrossRefGoogle Scholar
  130. 130.
    Chang PJ, Boonsiri J, Wang SS, Chen LY, Miller G (2010) Binding of RBP-Jkappa (CSL) protein to the promoter of the Kaposi’s sarcoma-associated herpesvirus ORF47 (gL) gene is a critical but not sufficient determinant of transactivation by ORF50 protein. Virology 398:38–48CrossRefGoogle Scholar
  131. 131.
    Wang SE, Wu FY, Fujimuro M, Zong J, Hayward SD, Hayward GS (2003) 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 77:600–623CrossRefGoogle Scholar
  132. 132.
    Guito J, Lukac DM (2012) KSHV Rta promoter specification and viral reactivation. Front Microbiol 3:30CrossRefGoogle Scholar
  133. 133.
    Sun Z, Jha HC, Pei YG, Robertson ES (2016) Major histocompatibility complex class II HLA-DRalpha is downregulated by Kaposi’s Sarcoma-associated herpesvirus-encoded lytic transactivator RTA and MARCH8. J Virol 90:8047–8058CrossRefGoogle Scholar
  134. 134.
    Chmura JC, Herold K, Ruffin A, Atuobi T, Fabiyi Y, Mitchell AE, Choi YB, Ehrlich ES (2017) The Itch ubiquitin ligase is required for KSHV RTA induced vFLIP degradation. Virology 501:119–126CrossRefGoogle Scholar
  135. 135.
    Ehrlich ES, Chmura JC, Smith JC, Kalu NN, Hayward GS (2014) KSHV RTA abolishes NFkappaB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome. PLoS ONE 9:e91359CrossRefGoogle Scholar
  136. 136.
    AuCoin DP, Colletti KS, Cei SA, Papouskova I, Tarrant M, Pari GS (2004) 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 318:542–555CrossRefGoogle Scholar
  137. 137.
    Wang Y, Li H, Chan MY, Zhu FX, Lukac DM, Yuan Y (2004) Kaposi’s sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: cis-acting requirements for replication and ori-Lyt-associated RNA transcription. J Virol 78:8615–8629CrossRefGoogle Scholar
  138. 138.
    Wakeman BS, Izumiya Y, Speck SH (2016) Identification of novel KSHV Orf50 transcripts: discovery of new RTA isoforms with variable transactivation potential. J VirolGoogle Scholar
  139. 139.
    Han Z, Swaminathan S (2006) Kaposi’s sarcoma-associated herpesvirus lytic gene ORF57 is essential for infectious virion production. J Virol 80:5251–5260CrossRefGoogle Scholar
  140. 140.
    Majerciak V, Yamanegi K, Allemand E, Kruhlak M, Krainer AR, Zheng ZM (2008) Kaposi’s sarcoma-associated herpesvirus ORF57 functions as a viral splicing factor and promotes expression of intron-containing viral lytic genes in spliceosome-mediated RNA splicing. J Virol 82:2792–2801CrossRefGoogle Scholar
  141. 141.
    Malik P, Blackbourn DJ, Cheng MF, Hayward GS, Clements JB (2004) Functional co-operation between the Kaposi’s sarcoma-associated herpesvirus ORF57 and ORF50 regulatory proteins. J Gen Virol 85:2155–2166CrossRefGoogle Scholar
  142. 142.
    Majerciak V, Zheng ZM (2015) KSHV ORF57, a protein of many faces. Viruses 7:604–633CrossRefGoogle Scholar
  143. 143.
    Pilkington GR, Majerciak V, Bear J, Uranishi H, Zheng ZM, Felber BK (2012) Kaposi’s sarcoma-associated herpesvirus ORF57 is not a bona fide export factor. J Virol 86:13089–13094CrossRefGoogle Scholar
  144. 144.
    Massimelli MJ, Kang JG, Majerciak V, Le SY, Liewehr DJ, Steinberg SM, Zheng ZM (2011) Stability of a long noncoding viral RNA depends on a 9-nt core element at the RNA 5′ end to interact with viral ORF57 and cellular PABPC1. Int J Biol Sci 7:1145–1160CrossRefGoogle Scholar
  145. 145.
    Sei E, Conrad NK (2011) Delineation of a core RNA element required for Kaposi’s sarcoma-associated herpesvirus ORF57 binding and activity. Virology 419:107–116CrossRefGoogle Scholar
  146. 146.
    Kang JG, Pripuzova N, Majerciak V, Kruhlak M, Le SY, Zheng ZM (2011) Kaposi’s sarcoma-associated herpesvirus ORF57 promotes escape of viral and human interleukin-6 from microRNA-mediated suppression. J Virol 85:2620–2630CrossRefGoogle Scholar
  147. 147.
    Boyne JR, Jackson BR, Taylor A, Macnab SA, Whitehouse A (2010) Kaposi’s sarcoma-associated herpesvirus ORF57 protein interacts with PYM to enhance translation of viral intronless mRNAs. EMBO J 29:1851–1864CrossRefGoogle Scholar
  148. 148.
    Lin SF, Robinson DR, Miller G, Kung HJ (1999) Kaposi’s sarcoma-associated herpesvirus encodes a bZIP protein with homology to BZLF1 of Epstein-Barr virus. J Virol 73:1909–1917Google Scholar
  149. 149.
    Purushothaman P, Uppal T, Verma SC (2015) Molecular biology of KSHV lytic reactivation. Viruses 7:116–153CrossRefGoogle Scholar
  150. 150.
    Martinez FP, Tang Q (2012) Leucine zipper domain is required for Kaposi sarcoma-associated herpesvirus (KSHV) K-bZIP protein to interact with histone deacetylase and is important for KSHV replication. J Biol Chem 287:15622–15634CrossRefGoogle Scholar
  151. 151.
    Izumiya Y, Ellison TJ, Yeh ET, Jung JU, Luciw PA, Kung HJ (2005) Kaposi’s sarcoma-associated herpesvirus K-bZIP represses gene transcription via SUMO modification. J Virol 79:9912–9925CrossRefGoogle Scholar
  152. 152.
    Chang PC, Izumiya Y, Wu CY, Fitzgerald LD, Campbell M, Ellison TJ, Lam KS, Luciw PA, Kung HJ (2010) Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a SUMO E3 ligase that is SIM-dependent and SUMO-2/3-specific. J Biol Chem 285:5266–5273CrossRefGoogle Scholar
  153. 153.
    Yang WS, Hsu HW, Campbell M, Cheng CY, Chang PC (2015) K-bZIP mediated SUMO-2/3 specific modification on the KSHV genome negatively regulates lytic gene expression and viral reactivation. PLoS Pathog 11:e1005051CrossRefGoogle Scholar
  154. 154.
    Yang WS, Campbell M, Chang PC (2017) SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication. PLoS Pathog 13:e1006216CrossRefGoogle Scholar
  155. 155.
    Rossetto C, Yamboliev I, Pari GS (2009) Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 K-bZIP modulates latency-associated nuclear protein-mediated suppression of lytic origin-dependent DNA synthesis. J Virol 83:8492–8501CrossRefGoogle Scholar
  156. 156.
    Izumiya Y, Izumiya C, Van Geelen A, Wang DH, Lam KS, Luciw PA, Kung HJ (2007) Kaposi’s sarcoma-associated herpesvirus-encoded protein kinase and its interaction with K-bZIP. J Virol 81:1072–1082CrossRefGoogle Scholar
  157. 157.
    Toth Z, Brulois K, Jung JU (2013) The chromatin landscape of Kaposi’s sarcoma-associated herpesvirus. Viruses 5:1346–1373CrossRefGoogle Scholar
  158. 158.
    Gwack Y, Baek HJ, Nakamura H, Lee SH, Meisterernst M, Roeder RG, Jung JU (2003) Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi’s sarcoma-associated herpesvirus RTA-mediated lytic reactivation. Mol Cell Biol 23:2055–2067CrossRefGoogle Scholar
  159. 159.
    Ye F, Zeng Y, Sha J, Jones T, Kuhne K, Wood C, Gao SJ (2016) High glucose induces reactivation of latent Kaposi’s sarcoma-associated herpesvirus. J Virol Aug 17. pii: JVI.01049-16. [Epub ahead of print]Google Scholar
  160. 160.
    Thakker S, Verma SC (2016) Co-infections and pathogenesis of KSHV-associated malignancies. Front Microbiol 7:151CrossRefGoogle Scholar
  161. 161.
    Merat R, Amara A, Lebbe C, de The H, Morel P, Saib A (2002) HIV-1 infection of primary effusion lymphoma cell line triggers Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation. Int J Cancer 97:791–795CrossRefGoogle Scholar
  162. 162.
    Zeng Y, Zhang X, Huang Z, Cheng L, Yao S, Qin D, Chen X, Tang Q, Lv Z, Zhang L, Lu C (2007) Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi’s sarcoma-associated herpesvirus: role of JAK/STAT signaling. J Virol 81:2401–2417CrossRefGoogle Scholar
  163. 163.
    Aoki Y, Tosato G (2004) HIV-1 Tat enhances Kaposi sarcoma-associated herpesvirus (KSHV) infectivity. Blood 104:810–814CrossRefGoogle Scholar
  164. 164.
    Spadavecchia S, Gonzalez-Lopez O, Carroll KD, Palmeri D, Lukac DM (2010) Convergence of Kaposi’s sarcoma-associated herpesvirus reactivation with Epstein-Barr virus latency and cellular growth mediated by the notch signaling pathway in coinfected cells. J Virol 84:10488–10500CrossRefGoogle Scholar
  165. 165.
    Jiang Y, Xu D, Zhao Y, Zhang L (2008) Mutual inhibition between Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr virus lytic replication initiators in dually-infected primary effusion lymphoma. PLoS ONE 3:e1569CrossRefGoogle Scholar
  166. 166.
    Lu C, Zeng Y, Huang Z, Huang L, Qian C, Tang G, Qin D (2005) Human herpesvirus 6 activates lytic cycle replication of Kaposi’s sarcoma-associated herpesvirus. Am J Pathol 166:173–183CrossRefGoogle Scholar
  167. 167.
    Tang Q, Qin D, Lv Z, Zhu X, Ma X, Yan Q, Zeng Y, Guo Y, Feng N, Lu C (2012) Herpes simplex virus type 2 triggers reactivation of Kaposi’s sarcoma-associated herpesvirus from latency and collaborates with HIV-1 Tat. PLoS ONE 7:e31652CrossRefGoogle Scholar
  168. 168.
    Blauvelt A (2001) Skin diseases associated with human herpesvirus 6, 7, and 8 infection. J Investig Dermatol Symp Proc 6:197–202CrossRefGoogle Scholar
  169. 169.
    Roupelieva M, Griffiths SJ, Kremmer E, Meisterernst M, Viejo-Borbolla A, Schulz T, Haas J (2010) Kaposi’s sarcoma-associated herpesvirus Lana-1 is a major activator of the serum response element and mitogen-activated protein kinase pathways via interactions with the mediator complex. J Gen Virol 91:1138–1149CrossRefGoogle Scholar
  170. 170.
    Vieira J, O’Hearn P, Kimball L, Chandran B, Corey L (2001) Activation of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) lytic replication by human cytomegalovirus. J Virol 75:1378–1386CrossRefGoogle Scholar
  171. 171.
    Wells R, Stensland L, Vieira J (2009) The human cytomegalovirus UL112-113 locus can activate the full Kaposi’s sarcoma-associated herpesvirus lytic replication cycle. J Virol 83:4695–4699CrossRefGoogle Scholar
  172. 172.
    Dai L, DeFee MR, Cao Y, Wen J, Wen X, Noverr MC, Qin Z (2014) Lipoteichoic acid (LTA) and lipopolysaccharides (LPS) from periodontal pathogenic bacteria facilitate oncogenic herpesvirus infection within primary oral cells. PLoS ONE 9:e101326CrossRefGoogle Scholar
  173. 173.
    Morris TL, Arnold RR, Webster-Cyriaque J (2007) Signaling cascades triggered by bacterial metabolic end products during reactivation of Kaposi’s sarcoma-associated herpesvirus. J Virol 81:6032–6042CrossRefGoogle Scholar
  174. 174.
    Yu X, Shahir AM, Sha J, Feng Z, Eapen B, Nithianantham S, Das B, Karn J, Weinberg A, Bissada NF, Ye F (2014) Short-chain fatty acids from periodontal pathogens suppress histone deacetylases, EZH2, and SUV39H1 to promote Kaposi’s sarcoma-associated herpesvirus replication. J Virol 88:4466–4479CrossRefGoogle Scholar
  175. 175.
    Davis DA, Rinderknecht AS, Zoeteweij JP, Aoki Y, Read-Connole EL, Tosato G, Blauvelt A, Yarchoan R (2001) Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus. Blood 97:3244–3250CrossRefGoogle Scholar
  176. 176.
    Haque M, Wang V, Davis DA, Zheng ZM, Yarchoan R (2006) Genetic organization and hypoxic activation of the Kaposi’s sarcoma-associated herpesvirus ORF34-37 gene cluster. J Virol 80:7037–7051CrossRefGoogle Scholar
  177. 177.
    Haque M, Davis DA, Wang V, Widmer I, Yarchoan R (2003) Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia. J Virol 77:6761–6768CrossRefGoogle Scholar
  178. 178.
    Veeranna RP, Haque M, Davis DA, Yang M, Yarchoan R (2012) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen induction by hypoxia and hypoxia-inducible factors. J Virol 86:1097–1108CrossRefGoogle Scholar
  179. 179.
    Cai Q, Lan K, Verma SC, Si H, Lin D, Robertson ES (2006) Kaposi’s sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions. J Virol 80:7965–7975CrossRefGoogle Scholar
  180. 180.
    Dalton-Griffin L, Wilson SJ, Kellam P (2009) X-box binding protein 1 contributes to induction of the Kaposi’s sarcoma-associated herpesvirus lytic cycle under hypoxic conditions. J Virol 83:7202–7209CrossRefGoogle Scholar
  181. 181.
    Yu F, Feng J, Harada JN, Chanda SK, Kenney SC, Sun R (2007) B cell terminal differentiation factor XBP-1 induces reactivation of Kaposi’s sarcoma-associated herpesvirus. FEBS Lett 581:3485–3488CrossRefGoogle Scholar
  182. 182.
    Zhang L, Zhu C, Guo Y, Wei F, Lu J, Qin J, Banerjee S, Wang J, Shang H, Verma SC, Yuan Z, Robertson ES, Cai Q (2014) Inhibition of KAP1 enhances hypoxia-induced Kaposi’s sarcoma-associated herpesvirus reactivation through RBP-Jkappa. J Virol 88:6873–6884CrossRefGoogle Scholar
  183. 183.
    Sun R, Liang D, Gao Y, Lan K (2014) Kaposi’s sarcoma-associated herpesvirus-encoded LANA interacts with host KAP1 to facilitate establishment of viral latency. J Virol 88:7331–7344CrossRefGoogle Scholar
  184. 184.
    Ye F, Zhou F, Bedolla RG, Jones T, Lei X, Kang T, Guadalupe M, Gao SJ (2011) Reactive oxygen species hydrogen peroxide mediates Kaposi’s sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog 7:e1002054CrossRefGoogle Scholar
  185. 185.
    Li X, Feng J, Sun R (2011) Oxidative stress induces reactivation of Kaposi’s sarcoma-associated herpesvirus and death of primary effusion lymphoma cells. J Virol 85:715–724CrossRefGoogle Scholar
  186. 186.
    Hesser CR, Karijolich J, Dominissini D, He C, Glaunsinger BA (2018) N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi’s sarcoma-associated herpesvirus infection. PLoS Pathog 14(4):e1006995Google Scholar
  187. 187.
    Tan B, Liu H, Zhang S, et al (2018) Viral and cellular N(6)-methyladenosine and N(6),2’-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat microbiol 3(1):108–120CrossRefGoogle Scholar
  188. 188.
    Du H, Zhao Y, He J, et al (2016) YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat commun 7:12626Google Scholar
  189. 189.
    Wang X, Lu Z, Gomez A, et al (2014) N6-methyladenosine-dependent regulation of messenger RNA stability. Nat 505(7481):117–120CrossRefGoogle Scholar
  190. 190.
    Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS (1997) KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15:1979–1985CrossRefGoogle Scholar
  191. 191.
    Hwang SW, Kim D, Jung JU, Lee HR (2017) KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production. Biochem Biophys Res Commun 486:700–705CrossRefGoogle Scholar
  192. 192.
    Giffin L, Damania B (2014) KSHV: pathways to tumorigenesis and persistent infection. Adv Virus Res 88:111–159CrossRefGoogle Scholar
  193. 193.
    Liang Q, Fu B, Wu F, Li X, Yuan Y, Zhu F (2012) ORF45 of Kaposi’s sarcoma-associated herpesvirus inhibits phosphorylation of interferon regulatory factor 7 by IKKepsilon and TBK1 as an alternative substrate. J Virol 86:10162–10172CrossRefGoogle Scholar
  194. 194.
    Yu Y, Wang SE, Hayward GS (2005) The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity 22:59–70CrossRefGoogle Scholar
  195. 195.
    Lefort S, Soucy-Faulkner A, Grandvaux N, Flamand L (2007) Binding of Kaposi’s sarcoma-associated herpesvirus K-bZIP to interferon-responsive factor 3 elements modulates antiviral gene expression. J Virol 81:10950–10960CrossRefGoogle Scholar
  196. 196.
    Bartee E, McCormack A, Fruh K (2006) Quantitative membrane proteomics reveals new cellular targets of viral immune modulators. PLoS Pathog 2:e107CrossRefGoogle Scholar
  197. 197.
    Li Q, Means R, Lang S, Jung JU (2007) Downregulation of gamma interferon receptor 1 by Kaposi’s sarcoma-associated herpesvirus K3 and K5. J Virol 81:2117–2127CrossRefGoogle Scholar
  198. 198.
    Lagos D, Vart RJ, Gratrix F, Westrop SJ, Emuss V, Wong PP, Robey R, Imami N, Bower M, Gotch F, Boshoff C (2008) Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus. Cell Host Microbe 4:470–483CrossRefGoogle Scholar
  199. 199.
    Jacobs SR, Gregory SM, West JA, Wollish AC, Bennett CL, Blackbourn DJ, Heise MT, Damania B (2013) The viral interferon regulatory factors of kaposi’s sarcoma-associated herpesvirus differ in their inhibition of interferon activation mediated by toll-like receptor 3. J Virol 87:798–806CrossRefGoogle Scholar
  200. 200.
    Jacobs SR, Stopford CM, West JA, Bennett CL, Giffin L, Damania B (2015) Kaposi’s Sarcoma-associated herpesvirus viral interferon regulatory factor 1 interacts with a member of the interferon-stimulated gene 15 pathway. J Virol 89:11572–11583CrossRefGoogle Scholar
  201. 201.
    Bussey KA, Reimer E, Todt H, Denker B, Gallo A, Konrad A, Ottinger M, Adler H, Sturzl M, Brune W, Brinkmann MM (2014) The gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus and murine gammaherpesvirus 68 modulate the Toll-like receptor-induced proinflammatory cytokine response. J Virol 88:9245–9259CrossRefGoogle Scholar
  202. 202.
    Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S, Reed JC, Ting JP, Damania B (2011) Discovery of a viral NLR homolog that inhibits the inflammasome. Science 331:330–334CrossRefGoogle Scholar
  203. 203.
    Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M, Buch A, Pich A, Brinkmann MM, Schulz TF (2016) Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS. Proc Natl Acad Sci U S A 113:E1034–43CrossRefGoogle Scholar
  204. 204.
    Wu JJ, Li W, Shao Y, Avey D, Fu B, Gillen J, Hand T, Ma S, Liu X, Miley W, Konrad A, Neipel F, Sturzl M, Whitby D, Li H, Zhu F (2015) Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein. Cell Host Microbe 18:333–344CrossRefGoogle Scholar
  205. 205.
    Ma Z, Jacobs SR, West JA, Stopford C, Zhang Z, Davis Z, Barber GN, Glaunsinger BA, Dittmer DP, Damania B (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A 112:E4306–15CrossRefGoogle Scholar
  206. 206.
    Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, Chandran B (2011) IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 9:363–375CrossRefGoogle Scholar
  207. 207.
    Roy A, Dutta D, Iqbal J, Pisano G, Gjyshi O, Ansari MA, Kumar B, Chandran B (2016) Nuclear innate immune DNA sensor IFI16 is degraded during lytic reactivation of Kaposi’s Sarcoma-Associated Herpesvirus (KSHV): role of IFI16 in maintenance of KSHV Latency. J Virol 90:8822–8841CrossRefGoogle Scholar
  208. 208.
    Areste C, Blackbourn DJ (2009) Modulation of the immune system by Kaposi’s sarcoma-associated herpesvirus. Trends Microbiol 17:119–129CrossRefGoogle Scholar
  209. 209.
    Lee MS, Jones T, Song DY, Jang JH, Jung JU, Gao SJ (2014) Exploitation of the complement system by oncogenic Kaposi’s sarcoma-associated herpesvirus for cell survival and persistent infection. PLoS Pathog 10:e1004412CrossRefGoogle Scholar
  210. 210.
    Thomas M, Wills M, Lehner PJ (2008) Natural killer cell evasion by an E3 ubiquitin ligase from Kaposi’s sarcoma-associated herpesvirus. Biochem Soc Trans 36:459–463CrossRefGoogle Scholar
  211. 211.
    Nachmani D, Stern-Ginossar N, Sarid R, Mandelboim O (2009) Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe 5:376–385CrossRefGoogle Scholar
  212. 212.
    Madrid AS, Ganem D (2012) Kaposi’s sarcoma-associated herpesvirus ORF54/dUTPase downregulates a ligand for the NK activating receptor NKp44. J Virol 86:8693–8704CrossRefGoogle Scholar
  213. 213.
    Robey RC, Mletzko S, Bower M, Meys R, Boffito M, Nelson M, Bunker CB, Gotch FM (2011) Ex-vivo recognition of late-lytic CD8 epitopes specific for Kaposi’s sarcoma-associated herpesvirus (KSHV) by HIV/KSHV-coinfected individuals. Viral Immunol 24:211–220CrossRefGoogle Scholar
  214. 214.
    Bihl F, Mosam A, Henry LN, Chisholm JV 3rd, Dollard S, Gumbi P, Cassol E, Page T, Mueller N, Kiepiela P, Martin JN, Coovadia HM, Scadden DT, Brander C (2007) Kaposi’s sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi’s sarcoma. Aids 21:1245–1252CrossRefGoogle Scholar
  215. 215.
    Miller G, Rigsby MO, Heston L, Grogan E, Sun R, Metroka C, Levy JA, Gao SJ, Chang Y, Moore P (1996) Antibodies to butyrate-inducible antigens of Kaposi’s sarcoma-associated herpesvirus in patients with HIV-1 infection. N Engl J Med 334:1292–1297CrossRefGoogle Scholar
  216. 216.
    Simpson GR, Schulz TF, Whitby D, Cook PM, Boshoff C, Rainbow L, Howard MR, Gao SJ, Bohenzky RA, Simmonds P, Lee C, de Ruiter A, Hatzakis A, Tedder RS, Weller IV, Weiss RA, Moore PS (1996) Prevalence of Kaposi’s sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 348:1133–1138CrossRefGoogle Scholar
  217. 217.
    Choi JK, Lee BS, Shim SN, Li M, Jung JU (2000) Identification of the novel K15 gene at the rightmost end of the Kaposi’s sarcoma-associated herpesvirus genome. J Virol 74:436–446CrossRefGoogle Scholar
  218. 218.
    Coscoy L, Ganem D (2001) A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation. J Clin Invest 107:1599–1606CrossRefGoogle Scholar
  219. 219.
    Ishido S, Wang C, Lee BS, Cohen GB, Jung JU (2000) Downregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. J Virol 74:5300–5309CrossRefGoogle Scholar
  220. 220.
    Brulois K, Toth Z, Wong LY, Feng P, Gao SJ, Ensser A, Jung JU (2014) Kaposi’s sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication. J Virol 88:9335–9349CrossRefGoogle Scholar
  221. 221.
    Brulois K, Jung JU (2014) Interplay between Kaposi’s sarcoma-associated herpesvirus and the innate immune system. Cytokine Growth Factor Rev 25:597–609CrossRefGoogle Scholar
  222. 222.
    Lagos D, Trotter MW, Vart RJ, Wang HW, Matthews NC, Hansen A, Flore O, Gotch F, Boshoff C (2007) Kaposi sarcoma herpesvirus-encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells. Blood 109:1550–1558CrossRefGoogle Scholar
  223. 223.
    Butler LM, Jeffery HC, Wheat RL, Long HM, Rae PC, Nash GB, Blackbourn DJ (2012) Kaposi’s sarcoma-associated herpesvirus inhibits expression and function of endothelial cell major histocompatibility complex class II via suppressor of cytokine signaling 3. J Virol 86:7158–7166CrossRefGoogle Scholar
  224. 224.
    Zuo J, Hislop AD, Leung CS, Sabbah S, Rowe M (2013) Kaposi’s sarcoma-associated herpesvirus-encoded viral IRF3 modulates major histocompatibility complex class II (MHC-II) antigen presentation through MHC-II transactivator-dependent and -independent mechanisms: implications for oncogenesis. J Virol 87:5340–5350CrossRefGoogle Scholar
  225. 225.
    Cirone M, Lucania G, Bergamo P, Trivedi P, Frati L, Faggioni A (2007) Human herpesvirus 8 (HHV-8) inhibits monocyte differentiation into dendritic cells and impairs their immunostimulatory activity. Immunol Lett 113:40–46CrossRefGoogle Scholar
  226. 226.
    Gregory SM, Wang L, West JA, Dittmer DP, Damania B (2012) Latent Kaposi’s sarcoma-associated herpesvirus infection of monocytes downregulates expression of adaptive immune response costimulatory receptors and proinflammatory cytokines. J Virol 86:3916–3923CrossRefGoogle Scholar
  227. 227.
    Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, Libermann T, Dezube BJ, Fingeroth JD, Detmar M (2004) Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36:683–685CrossRefGoogle Scholar
  228. 228.
    Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Makinen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C (2004) Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi’s sarcoma. Nat Genet 36:687–693CrossRefGoogle Scholar
  229. 229.
    Flore O, Rafii S, Ely S, O’Leary JJ, Hyjek EM, Cesarman E (1998) Transformation of primary human endothelial cells by Kaposi’s sarcoma-associated herpesvirus. Nature 394:588–592CrossRefGoogle Scholar
  230. 230.
    Wang L, Damania B (2008) Kaposi’s sarcoma-associated herpesvirus confers a survival advantage to endothelial cells. Cancer Res 68:4640–4648CrossRefGoogle Scholar
  231. 231.
    Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, Duran EM, Asgari Z, Hooper AT, La Perle KM, Hilsher C, Gao SJ, Dittmer DP, Rafii S, Mesri EA (2007) In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi’s sarcoma. Cancer Cell 11:245–258CrossRefGoogle Scholar
  232. 232.
    Lee MS, Yuan H, Jeon H, Zhu Y, Yoo S, Shi S, Krueger B, Renne R, Lu C, Jung JU, Gao SJ (2016) Human mesenchymal stem cells of diverse origins support persistent infection with Kaposi’s sarcoma-associated herpesvirus and manifest distinct angiogenic, invasive, and transforming phenotypes. MBio 7:e02109–15Google Scholar
  233. 233.
    Wu W, Vieira J, Fiore N, Banerjee P, Sieburg M, Rochford R, Harrington W Jr, Feuer G (2006) KSHV/HHV-8 infection of human hematopoietic progenitor (CD34+) cells: persistence of infection during hematopoiesis in vitro and in vivo. Blood 108:141–151CrossRefGoogle Scholar
  234. 234.
    Di Bartolo DL, Cannon M, Liu YF, Renne R, Chadburn A, Boshoff C, Cesarman E (2008) KSHV LANA inhibits TGF-beta signaling through epigenetic silencing of the TGF-beta type II receptor. Blood 111:4731–4740CrossRefGoogle Scholar
  235. 235.
    Santag S, Jager W, Karsten CB, Kati S, Pietrek M, Steinemann D, Sarek G, Ojala PM, Schulz TF (2013) Recruitment of the tumour suppressor protein p73 by Kaposi’s sarcoma herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells. Oncogene 32:3676–3685CrossRefGoogle Scholar
  236. 236.
    Friborg J Jr, Kong W, Hottiger MO, Nabel GJ (1999) p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402:889–894CrossRefGoogle Scholar
  237. 237.
    Radkov SA, Kellam P, Boshoff C (2000) 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 6:1121–1127CrossRefGoogle Scholar
  238. 238.
    Lu J, Verma SC, Murakami M, Cai Q, Kumar P, Xiao B, Robertson ES (2009) Latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus (KSHV) upregulates survivin expression in KSHV-Associated B-lymphoma cells and contributes to their proliferation. J Virol 83:7129–7141CrossRefGoogle Scholar
  239. 239.
    Bubman D, Guasparri I, Cesarman E (2007) Deregulation of c-Myc in primary effusion lymphoma by Kaposi’s sarcoma herpesvirus latency-associated nuclear antigen. Oncogene 26:4979–4986CrossRefGoogle Scholar
  240. 240.
    Qin Z, Dai L, Slomiany MG, Toole BP, Parsons C (2010) Direct activation of emmprin and associated pathogenesis by an oncogenic herpesvirus. Cancer Res 70:3884–3889CrossRefGoogle Scholar
  241. 241.
    Liu J, Martin HJ, Liao G, Hayward SD (2007) The Kaposi’s sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol 81:10451–10459CrossRefGoogle Scholar
  242. 242.
    Liang D, Hu H, Li S, Dong J, Wang X, Wang Y, He L, He Z, Gao Y, Gao SJ, Lan K (2014) Oncogenic herpesvirus KSHV Hijacks BMP-Smad1-Id signaling to promote tumorigenesis. PLoS Pathog 10:e1004253CrossRefGoogle Scholar
  243. 243.
    Jha HC, Sun Z, Upadhyay SK, El-Naccache DW, Singh RK, Sahu SK, Robertson ES (2016) KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation. PLoS Pathog 12:e1005801CrossRefGoogle Scholar
  244. 244.
    Zhu Y, Ramos da Silva S, He M, Liang Q, Lu C, Feng P, Jung JU, Gao SJ (2016) An oncogenic virus promotes cell survival and cellular transformation by suppressing glycolysis. PLoS Pathog 12:e1005648CrossRefGoogle Scholar
  245. 245.
    Ballon G, Chen K, Perez R, Tam W, Cesarman E (2011) Kaposi’s sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest 121:1141–1153CrossRefGoogle Scholar
  246. 246.
    Moody R, Zhu Y, Huang Y, Cui X, Jones T, Bedolla R, Lei X, Bai Z, Gao SJ (2013) KSHV microRNAs mediate cellular transformation and tumorigenesis by redundantly targeting cell growth and survival pathways. PLoS Pathog 9:e1003857CrossRefGoogle Scholar
  247. 247.
    Zhi H, Zahoor MA, Shudofsky AM, Giam CZ (2015) KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-kappaB hyperactivation. Oncogene 34:496–505CrossRefGoogle Scholar
  248. 248.
    Godden-Kent D, Talbot SJ, Boshoff C, Chang Y, Moore P, Weiss RA, Mittnacht S (1997) The cyclin encoded by Kaposi’s sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. J Virol 71:4193–4198Google Scholar
  249. 249.
    Swanton C, Mann DJ, Fleckenstein B, Neipel F, Peters G, Jones N (1997) Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature 390:184–187CrossRefGoogle Scholar
  250. 250.
    Verschuren EW, Klefstrom J, Evan GI, Jones N (2002) The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell 2:229–241CrossRefGoogle Scholar
  251. 251.
    Jones T, Ramos da Silva S, Bedolla R, Ye F, Zhou F, Gao SJ (2014) Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition. Cell Cycle 13:845–858CrossRefGoogle Scholar
  252. 252.
    Seo T, Park J, Lee D, Hwang SG, Choe J (2001) Viral interferon regulatory factor 1 of Kaposi’s sarcoma-associated herpesvirus binds to p53 and represses p53-dependent transcription and apoptosis. J Virol 75:6193–6198CrossRefGoogle Scholar
  253. 253.
    Seo T, Park J, Choe J (2005) Kaposi’s sarcoma-associated herpesvirus viral IFN regulatory factor 1 inhibits transforming growth factor-beta signaling. Cancer Res 65:1738–1747CrossRefGoogle Scholar
  254. 254.
    Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA (1998) G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391:86–89CrossRefGoogle Scholar
  255. 255.
    Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, Sullivan L, Jenh CH, Narula SK, Chensue SW, Lira SA (2000) Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi’s sarcoma. J Exp Med 191:445–454CrossRefGoogle Scholar
  256. 256.
    Krause CJ, Popp O, Thirunarayanan N, Dittmar G, Lipp M, Muller G (2016) MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR. Oncotarget 7:10414–10432CrossRefGoogle Scholar
  257. 257.
    Martin D, Galisteo R, Molinolo AA, Wetzker R, Hirsch E, Gutkind JS (2011) PI3Kgamma mediates kaposi’s sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 19:805–813CrossRefGoogle Scholar
  258. 258.
    Martin D, Nguyen Q, Molinolo A, Gutkind JS (2014) Accumulation of dephosphorylated 4EBP after mTOR inhibition with rapamycin is sufficient to disrupt paracrine transformation by the KSHV vGPCR oncogene. Oncogene 33:2405–2412CrossRefGoogle Scholar
  259. 259.
    Wu J, Xu Y, Mo D, Huang P, Sun R, Huang L, Pan S, Xu J (2014) Kaposi’s sarcoma-associated herpesvirus (KSHV) vIL-6 promotes cell proliferation and migration by upregulating DNMT1 via STAT3 activation. PLoS ONE 9:e93478CrossRefGoogle Scholar
  260. 260.
    Hideshima T, Chauhan D, Teoh G, Raje N, Treon SP, Tai YT, Shima Y, Anderson KC (2000) Characterization of signaling cascades triggered by human interleukin-6 versus Kaposi’s sarcoma-associated herpes virus-encoded viral interleukin 6. Clin Cancer Res 6:1180–1189Google Scholar
  261. 261.
    Chen D, Choi YB, Sandford G, Nicholas J (2009) Determinants of secretion and intracellular localization of human herpesvirus 8 interleukin-6. J Virol 83:6874–6882CrossRefGoogle Scholar
  262. 262.
    Chen D, Cousins E, Sandford G, Nicholas J (2012) Human herpesvirus 8 viral interleukin-6 interacts with splice variant 2 of vitamin K epoxide reductase complex subunit 1. J Virol 86:1577–1588CrossRefGoogle Scholar
  263. 263.
    Lee H, Veazey R, Williams K, Li M, Guo J, Neipel F, Fleckenstein B, Lackner A, Desrosiers RC, Jung JU (1998) Deregulation of cell growth by the K1 gene of Kaposi’s sarcoma-associated herpesvirus. Nat Med 4:435–440CrossRefGoogle Scholar
  264. 264.
    Tomlinson CC, Damania B (2004) The K1 protein of Kaposi’s sarcoma-associated herpesvirus activates the Akt signaling pathway. J Virol 78:1918–1927CrossRefGoogle Scholar
  265. 265.
    Anders PM, Zhang Z, Bhende PM, Giffin L, Damania B (2016) The KSHV K1 protein modulates AMPK function to enhance cell survival. PLoS Pathog 12:e1005985CrossRefGoogle Scholar
  266. 266.
    Tolani B, Gopalakrishnan R, Punj V, Matta H, Chaudhary PM (2014) Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene 33:2928–2937CrossRefGoogle Scholar
  267. 267.
    Aoki Y, Feldman GM, Tosato G (2003) Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101:1535–1542CrossRefGoogle Scholar
  268. 268.
    He M, Tan B, Vasan K, Yuan H, Cheng F, Ramos da Silva S, Lu C, Gao SJ (2017) SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells. J PatholGoogle Scholar
  269. 269.
    He M, Yuan H, Tan B, Bai R, Kim HS, Bae S, Che L, Kim JS, Gao SJ (2016) SIRT1-mediated downregulation of p27Kip1 is essential for overcoming contact inhibition of Kaposi’s sarcoma-associated herpesvirus transformed cells. Oncotarget 7:75698–75711Google Scholar
  270. 270.
    Bhatt S, Ashlock BM, Toomey NL, Diaz LA, Mesri EA, Lossos IS, Ramos JC (2013) Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest 123:2616–2628CrossRefGoogle Scholar
  271. 271.
    Chaisuparat R, Hu J, Jham BC, Knight ZA, Shokat KM, Montaner S (2008) Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi’s sarcoma. Cancer Res 68:8361–8368CrossRefGoogle Scholar
  272. 272.
    Dai L, Trillo-Tinoco J, Cao Y, Bonstaff K, Doyle L, Del Valle L, Whitby D, Parsons C, Reiss K, Zabaleta J, Qin Z (2015) Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood 126:2821–2831CrossRefGoogle Scholar
  273. 273.
    Lam BQ, Dai L, Li L, Qiao J, Lin Z, Qin Z (2017) Molecular mechanisms of activating c-MET in KSHV+ primary effusion lymphoma. Oncotarget 8:18373–18380Google Scholar
  274. 274.
    Korniluk A, Koper O, Kemona H, Dymicka-Piekarska V (2017) From inflammation to cancer. Ir J Med Sci 186:57–62CrossRefGoogle Scholar
  275. 275.
    Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22:33–40CrossRefGoogle Scholar
  276. 276.
    Riva G, Barozzi P, Torelli G, Luppi M (2010) Immunological and inflammatory features of Kaposi’s sarcoma and other Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8-associated neoplasias. AIDS Rev 12:40–51Google Scholar
  277. 277.
    Guedes F, de Andrade HF Jr, Fernandes ER, Tuon FF, Brasil RA, Pagliari C, Duarte MI (2008) The effects of human herpesvirus 8 infection and interferon-gamma response in cutaneous lesions of Kaposi sarcoma differ among human immunodeficiency virus-infected and uninfected individuals. Br J Dermatol 159:839–846CrossRefGoogle Scholar
  278. 278.
    Breuer-McHam JN, Ledbetter LS, Sarris AH, Duvic M (2000) Cytokine expression patterns distinguish HIV associated skin diseases. Exp Dermatol 9:341–350CrossRefGoogle Scholar
  279. 279.
    Desnoyer A, Dupin N, Assoumou L, Carlotti A, Gaudin F, Deback C, Peytavin G, Marcelin AG, Boue F, Balabanian K, Pourcher V, group A. L. t. (2016) Expression pattern of the CXCL12/CXCR4-CXCR7 trio in Kaposi sarcoma skin lesions. Br J Dermatol 175:1251–1262CrossRefGoogle Scholar
  280. 280.
    DiMaio TA, Gutierrez KD, Lagunoff M (2014) Kaposi’s sarcoma-associated herpesvirus downregulates transforming growth factor beta2 to promote enhanced stability of capillary-like tube formation. J Virol 88:14301–14309CrossRefGoogle Scholar
  281. 281.
    Douglas JL, Gustin JK, Moses AV, Dezube BJ, Pantanowitz L (2010) Kaposi’s sarcoma pathogenesis: a triad of viral infection, oncogenesis and chronic inflammation. Transl Biomed 1. pii: 172Google Scholar
  282. 282.
    Dai L, Bratoeva M, Toole BP, Qin Z, Parsons C (2012) KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction. Int J Cancer 131:834–843CrossRefGoogle Scholar
  283. 283.
    Wang X, He Z, Xia T, Li X, Liang D, Lin X, Wen H, Lan K (2014) Latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus promotes angiogenesis through targeting notch signaling effector Hey1. Cancer Res 74:2026–2037CrossRefGoogle Scholar
  284. 284.
    Cheng F, Pekkonen P, Laurinavicius S, Sugiyama N, Henderson S, Gunther T, Rantanen V, Kaivanto E, Aavikko M, Sarek G, Hautaniemi S, Biberfeld P, Aaltonen L, Grundhoff A, Boshoff C, Alitalo K, Lehti K, Ojala PM (2011) KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition. Cell Host Microbe 10:577–590CrossRefGoogle Scholar
  285. 285.
    Zaldumbide A, Ossevoort M, Wiertz EJ, Hoeben RC (2007) In cis inhibition of antigen processing by the latency-associated nuclear antigen I of Kaposi sarcoma herpes virus. Mol Immunol 44:1352–1360CrossRefGoogle Scholar
  286. 286.
    Thakker S, Purushothaman P, Gupta N, Challa S, Cai Q, Verma SC (2015) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen inhibits major histocompatibility complex class II expression by disrupting enhanceosome assembly through binding with the regulatory factor X complex. J Virol 89:5536–5556CrossRefGoogle Scholar
  287. 287.
    Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM (2002) The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem 277:13745–13751CrossRefGoogle Scholar
  288. 288.
    Matta H, Chaudhary PM (2004) 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 101:9399–9404CrossRefGoogle Scholar
  289. 289.
    Sharma-Walia N, Patel K, Chandran K, Marginean A, Bottero V, Kerur N, Paul AG (2012) COX-2/PGE2: molecular ambassadors of Kaposi’s sarcoma-associated herpes virus oncoprotein-v-FLIP. Oncogenesis 1:e5CrossRefGoogle Scholar
  290. 290.
    Guo Y, Li W, Qin J, Lu C, Fan W (2017) Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded microRNAs promote matrix metalloproteinases (MMPs) expression and pro-angiogenic cytokine secretion in endothelial cells. J Med Virol 89:1274–1280CrossRefGoogle Scholar
  291. 291.
    Breen EC (2007) VEGF in biological control. J Cell Biochem 102:1358–1367CrossRefGoogle Scholar
  292. 292.
    Hu M, Wang C, Li W, Lu W, Bai Z, Qin D, Yan Q, Zhu J, Krueger BJ, Renne R, Gao SJ, Lu C (2015) A KSHV microRNA directly targets G protein-coupled receptor Kinase 2 to promote the migration and invasion of endothelial cells by inducing CXCR2 and activating AKT signaling. PLoS Pathog 11:e1005171CrossRefGoogle Scholar
  293. 293.
    Li W, Jia X, Shen C, Zhang M, Xu J, Shang Y, Zhu K, Hu M, Yan Q, Qin D, Lee MS, Zhu J, Lu H, Krueger BJ, Renne R, Gao SJ, Lu C (2016) A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway. Oncotarget 7:32286–32305Google Scholar
  294. 294.
    Li W, Yan Q, Ding X, Shen C, Hu M, Zhu Y, Qin D, Lu H, Krueger BJ, Renne R, Gao SJ, Lu C (2016) The SH3BGR/STAT3 pathway regulates cell migration and angiogenesis induced by a gammaherpesvirus microRNA. PLoS Pathog 12:e1005605CrossRefGoogle Scholar
  295. 295.
    Li W, Hu M, Wang C, Lu H, Chen F, Xu J, Shang Y, Wang F, Qin J, Yan Q, Krueger BJ, Renne R, Gao SJ, Lu C (2017) A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling. Oncogene. May 22.  https://doi.org/10.1038/onc.2017.139. [Epub ahead of print]CrossRefGoogle Scholar
  296. 296.
    Liu Y, Sun R, Lin X, Liang D, Deng Q, Lan K (2012) Kaposi’s sarcoma-associated herpesvirus-encoded microRNA miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5. J Virol 86:1372–1381CrossRefGoogle Scholar
  297. 297.
    Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, Baker HV, Renne R (2007) Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog 3:e65CrossRefGoogle Scholar
  298. 298.
    Yoo J, Kang J, Lee HN, Aguilar B, Kafka D, Lee S, Choi I, Lee J, Ramu S, Haas J, Koh CJ, Hong YK (2010) Kaposin-B enhances the PROX1 mRNA stability during lymphatic reprogramming of vascular endothelial cells by Kaposi’s sarcoma herpes virus. PLoS Pathog 6:e1001046CrossRefGoogle Scholar
  299. 299.
    McCormick C, Ganem D (2005) The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 307:739–741CrossRefGoogle Scholar
  300. 300.
    Chang HC, Hsieh TH, Lee YW, Tsai CF, Tsai YN, Cheng CC, Wang HW (2016) c-Myc and viral cofactor Kaposin B co-operate to elicit angiogenesis through modulating miRNome traits of endothelial cells. BMC Syst Biol 10(Suppl 1):1CrossRefGoogle Scholar
  301. 301.
    Shin YC, Joo CH, Gack MU, Lee HR, Jung JU (2008) Kaposi’s sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1 alpha to induce vascular endothelial growth factor expression. Cancer Res 68:1751–1759CrossRefGoogle Scholar
  302. 302.
    Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF (2003) Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi’s sarcoma-associated herpesvirus K15 membrane protein. J Virol 77:9346–9358CrossRefGoogle Scholar
  303. 303.
    Cho NH, Choi YK, Choi JK (2008) Multi-transmembrane protein K15 of Kaposi’s sarcoma-associated herpesvirus targets Lyn kinase in the membrane raft and induces NFAT/AP1 activities. Exp Mol Med 40:565–573CrossRefGoogle Scholar
  304. 304.
    Bala K, Bosco R, Gramolelli S, Haas DA, Kati S, Pietrek M, Havemeier A, Yakushko Y, Singh VV, Dittrich-Breiholz O, Kracht M, Schulz TF (2012) Kaposi’s sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathog 8:e1002927CrossRefGoogle Scholar
  305. 305.
    Lee BS, Lee SH, Feng P, Chang H, Cho NH, Jung JU (2005) Characterization of the Kaposi’s sarcoma-associated herpesvirus K1 signalosome. J Virol 79:12173–12184CrossRefGoogle Scholar
  306. 306.
    Wang L, Wakisaka N, Tomlinson CC, DeWire SM, Krall S, Pagano JS, Damania B (2004) The Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors. Cancer Res 64:2774–2781CrossRefGoogle Scholar
  307. 307.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744CrossRefGoogle Scholar
  308. 308.
    Yao S, Hu M, Hao T, Li W, Xue X, Xue M, Zhu X, Zhou F, Qin D, Yan Q, Zhu J, Gao SJ, Lu C (2015) MiRNA-891a-5p mediates HIV-1 Tat and KSHV Orf-K1 synergistic induction of angiogenesis by activating NF-kappaB signaling. Nucleic Acids Res 43:9362–9378CrossRefGoogle Scholar
  309. 309.
    Xue M, Yao S, Hu M, Li W, Hao T, Zhou F, Zhu X, Lu H, Qin D, Yan Q, Zhu J, Gao SJ, Lu C (2014) HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway. Nucleic Acids Res 42:9862–9879CrossRefGoogle Scholar
  310. 310.
    Mansouri M, Rose PP, Moses AV, Fruh K (2008) Remodeling of endothelial adherens junctions by Kaposi’s sarcoma-associated herpesvirus. J Virol 82:9615–9628CrossRefGoogle Scholar
  311. 311.
    Aoki Y, Jaffe ES, Chang Y, Jones K, Teruya-Feldstein J, Moore PS, Tosato G (1999) Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93:4034–4043Google Scholar
  312. 312.
    Cannon M (2007) The KSHV and other human herpesviral G protein-coupled receptors. Curr Top Microbiol Immunol 312:137–156Google Scholar
  313. 313.
    de Munnik SM, Smit MJ, Leurs R, Vischer HF (2015) Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors. Front Pharmacol 6:40CrossRefGoogle Scholar
  314. 314.
    Pati S, Cavrois M, Guo HG, Foulke JS Jr, Kim J, Feldman RA, Reitz M (2001) Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi’s sarcoma pathogenesis. J Virol 75:8660–8673CrossRefGoogle Scholar
  315. 315.
    Choi YB, Nicholas J (2008) Autocrine and paracrine promotion of cell survival and virus replication by human herpesvirus 8 chemokines. J Virol 82:6501–6513CrossRefGoogle Scholar
  316. 316.
    Stine JT, Wood C, Hill M, Epp A, Raport CJ, Schweickart VL, Endo Y, Sasaki T, Simmons G, Boshoff C, Clapham P, Chang Y, Moore P, Gray PW, Chantry D (2000) KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood 95:1151–1157Google Scholar
  317. 317.
    Nicholas J (2010) Human herpesvirus 8-encoded cytokines. Future Virol 5:197–206CrossRefGoogle Scholar
  318. 318.
    Szpakowska M, Chevigne A (2016) vCCL2/vMIP-II, the viral master KEYmokine. J Leukoc Biol 99:893–900CrossRefGoogle Scholar
  319. 319.
    Delgado T, Carroll PA, Punjabi AS, Margineantu D, Hockenbery DM, Lagunoff M (2010) Induction of the Warburg effect by Kaposi’s sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells. Proc Natl Acad Sci U S A 107:10696–10701CrossRefGoogle Scholar
  320. 320.
    Ma T, Patel H, Babapoor-Farrokhran S, Franklin R, Semenza GL, Sodhi A, Montaner S (2015) KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis 18:477–488CrossRefGoogle Scholar
  321. 321.
    Daye D, Wellen KE (2012) Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol 23:362–369CrossRefGoogle Scholar
  322. 322.
    Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK (2012) Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336:1040–1044CrossRefGoogle Scholar
  323. 323.
    Sanchez EL, Carroll PA, Thalhofer AB, Lagunoff M (2015) Latent KSHV infected endothelial cells are glutamine addicted and require glutaminolysis for survival. PLoS Pathog 11:e1005052CrossRefGoogle Scholar
  324. 324.
    Zhu Y, Li TT, Ramos da Silva S, Lee JJ, Lu C, Eoh HJ, Jung JU, Gao SJ (2017) A critical role of glutamine γ-nitrogen for nucleotide biosynthesis in cancer cells hijacked by an oncogenic virus mBio, submittedGoogle Scholar
  325. 325.
    Delgado T, Sanchez EL, Camarda R, Lagunoff M (2012) Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS Pathog 8:e1002866CrossRefGoogle Scholar
  326. 326.
    Sychev ZE, Hu A, DiMaio TA, Gitter A, Camp ND, Noble WS, Wolf-Yadlin A, Lagunoff M (2017) Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism. PLoS Pathog 13:e1006256CrossRefGoogle Scholar
  327. 327.
    Bhatt AP, Jacobs SR, Freemerman AJ, Makowski L, Rathmell JC, Dittmer DP, Damania B (2012) Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma. Proc Natl Acad Sci U S A 109:11818–11823CrossRefGoogle Scholar
  328. 328.
    Sanchez EL, Pulliam TH, Dimaio TA, Thalhofer AB, Delgado T, Lagunoff M (2017) Glycolysis, glutaminolysis, and fatty acid synthesis are required for distinct stages of Kaposi’s sarcoma-associated herpesvirus lytic replication. J Virol 91: Apr 28;91(10). pii: e02237-16.  https://doi.org/10.1128/jvi.02237-16. Print 2017 May 15
  329. 329.
    Cianfrocca M, Lee S, Von Roenn J, Tulpule A, Dezube BJ, Aboulafia DM, Ambinder RF, Lee JY, Krown SE, Sparano JA (2010) Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy. Cancer 116:3969–3977CrossRefGoogle Scholar
  330. 330.
    Pinzone MR, Berretta M, Cacopardo B, Nunnari G (2015) Epstein-barr virus- and Kaposi sarcoma-associated herpesvirus-related malignancies in the setting of human immunodeficiency virus infection. Semin Oncol 42:258–271CrossRefGoogle Scholar
  331. 331.
    Roy D, Sin SH, Lucas A, Venkataramanan R, Wang L, Eason A, Chavakula V, Hilton IB, Tamburro KM, Damania B, Dittmer DP (2013) mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Res 73:2235–2246CrossRefGoogle Scholar
  332. 332.
    Sin SH, Roy D, Wang L, Staudt MR, Fakhari FD, Patel DD, Henry D, Harrington WJ Jr, Damania BA, Dittmer DP (2007) Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 109:2165–2173CrossRefGoogle Scholar
  333. 333.
    Petre CE, Sin SH, Dittmer DP (2007) Functional p53 signaling in Kaposi’s sarcoma-associated herpesvirus lymphomas: implications for therapy. J Virol 81:1912–1922CrossRefGoogle Scholar
  334. 334.
    Sarek G, Kurki S, Enback J, Iotzova G, Haas J, Laakkonen P, Laiho M, Ojala PM (2007) Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. J Clin Invest 117:1019–1028CrossRefGoogle Scholar
  335. 335.
    Ye F, Lattif AA, Xie J, Weinberg A, Gao S (2012) Nutlin-3 induces apoptosis, disrupts viral latency and inhibits expression of angiopoietin-2 in Kaposi sarcoma tumor cells. Cell Cycle 11:1393–1399CrossRefGoogle Scholar
  336. 336.
    Uldrick TS, Wyvill KM, Kumar P, O’Mahony D, Bernstein W, Aleman K, Polizzotto MN, Steinberg SM, Pittaluga S, Marshall V, Whitby D, Little RF, Yarchoan R (2012) Phase II study of bevacizumab in patients with HIV-associated Kaposi’s sarcoma receiving antiretroviral therapy. J Clin Oncol 30:1476–1483CrossRefGoogle Scholar
  337. 337.
    Koon HB, Krown SE, Lee JY, Honda K, Rapisuwon S, Wang Z, Aboulafia D, Reid EG, Rudek MA, Dezube BJ, Noy A (2014) Phase II trial of imatinib in AIDS-associated Kaposi’s sarcoma: AIDS Malignancy Consortium Protocol 042. J Clin Oncol 32:402–408CrossRefGoogle Scholar
  338. 338.
    van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A, Simpson D, Capra M, Liu T, Hsieh RK, Goh YT, Zhu J, Cho SG, Ren H, Cavet J, Bandekar R, Rothman M, Puchalski TA, Reddy M, van de Velde H, Vermeulen J, Casper C (2014) Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 15:966–974CrossRefGoogle Scholar
  339. 339.
    Dittmer DP, Damania B (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126:3165–3175CrossRefGoogle Scholar
  340. 340.
    Bhatt AP, Bhende PM, Sin SH, Roy D, Dittmer DP, Damania B (2010) Dual inhibition of PI3 K and mTOR inhibits autocrine and paracrine proliferative loops in PI3 K/Akt/mTOR-addicted lymphomas. Blood 115:4455–4463CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Meilan He
    • 1
  • Fan Cheng
    • 1
  • Suzane Ramos da Silva
    • 1
  • Brandon Tan
    • 1
  • Océane Sorel
    • 1
  • Marion Gruffaz
    • 1
  • Tingting Li
    • 1
  • Shou-Jiang Gao
    • 1
  1. 1.Department of Molecular Microbiology and Immunology, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

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