KSHV Genome Replication and Maintenance in Latency

  • Keiji UedaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1045)


Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is the eighth human herpesvirus found by Yuan Chang and Patrick Moore, 1992. It is a Rhadinovirus belonging to the gamma herpesvirus subfamily. As known for many gamma herpesviruses, KSHV is also well-correlated to several cancer formations such as Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease. Different from the other herpesvirus subfamily, gamma herpesviruses establish latency as a default infection strategy when they infect to the target cells, as KSHV is present as the latent form in the related cancers. In the latency, the virus expresses a limited number of the genes such as latency-associated nuclear antigen (LANA), v-cyclin (v-CYC, ORF72), v-FLIP (K13), kaposin (K12), and 25 microRNAs (K-miRNAs). The virus replicates according to cellular replication machinery with a viral replication origin (ori-P) and LANA. Then, the replicated genome is segregated equally to daughter cells by appearance to maintain the virus genome copy number per cell. The virus makes the most use of cellular machinery to achieve this end. In this chapter, I would like to review KSHV replication and gene expression in the latency and discuss.


Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) Latency ori-P LANA (ORF73) v-cyclin (v-CYC, ORF72) v-FLIP (K13) Kaposin (K12) Kaposi’s sarcoma (KS) Primary effusion lymphoma (PEL) Multicentric Castleman’s disease (MCD) 


  1. Ambroziak JA, Blackbourn DJ, Herndier BG, Glogau RG, Gullett JH, McDonald AR, Lennette ET, Levy JA (1995) Herpes-like sequences in HIV-infected and uninfected Kaposi’s sarcoma patients. Science 268(5210):582–583CrossRefPubMedGoogle Scholar
  2. Andreoni M, Sarmati L, Nicastri E, El Sawaf G, El Zalabani M, Uccella I, Bugarini R, Parisi SG, Rezza G (2002) Primary human herpesvirus 8 infection in immunocompetent children. JAMA 287(10):1295–1300CrossRefPubMedGoogle Scholar
  3. 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(7):3250–3258CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ballestas ME, Kaye KM (2011) The latency-associated nuclear antigen, a multifunctional protein central to Kaposi’s sarcoma-associated herpesvirus latency. Future Microbiol 6(12):1399–1413. CrossRefPubMedGoogle Scholar
  5. Ballestas ME, Chatis PA, Kaye KM (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284(5414):641–644CrossRefPubMedGoogle Scholar
  6. Ballon G, Chen K, Perez R, Tam W, Cesarman E (2011) Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest 121(3):1141–1153. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boshoff C, Chang Y (2001) Kaposi’s sarcoma-associated herpesvirus: a new DNA tumor virus. Annu Rev Med 52:453–470CrossRefPubMedGoogle Scholar
  8. Boshoff C, Weiss RA (1998) Kaposi’s sarcoma-associated herpesvirus. Adv Cancer Res 75:57–86CrossRefPubMedGoogle Scholar
  9. Boshoff C, Weiss RA (2001) Epidemiology and pathogenesis of Kaposi’s sarcoma-associated herpesvirus. Philos Trans R Soc Lond Ser B Biol Sci 356(1408):517–534CrossRefGoogle Scholar
  10. Boss IW, Plaisance KB, Renne R (2009) Role of virus-encoded microRNAs in herpesvirus biology. Trends Microbiol 17(12):544–553. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Brown HJ, Song MJ, Deng H, Wu TT, Cheng G, Sun R (2003) NF-kappaB inhibits gammaherpesvirus lytic replication. J Virol 77(15):8532–8540CrossRefPubMedPubMedCentralGoogle Scholar
  12. Burysek L, Pitha PM (2001) Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. J Virol 75(5):2345–2352CrossRefPubMedGoogle Scholar
  13. 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(18):1186–1191CrossRefGoogle Scholar
  14. 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(5192):1865–1869CrossRefGoogle Scholar
  15. Cieniewicz B, Santana AL, Minkah N, Krug LT (2016) Interplay of murine Gammaherpesvirus 68 with NF-kappaB signaling of the host. Front Microbiol 7:1202. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cotter MA 2nd, Robertson ES (1999) The latency-associated nuclear antigen tethers the Kaposi’s sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology 264(2):254–264CrossRefPubMedGoogle Scholar
  17. Damania BA, Cesarman E (2013) In: Knipe DMHPM (ed) Kaposi’s sarcoma-associated herpesvirus, Fields virology, vol 2, 6th edn. Lippincott Willamas and Wilkins, Philadelphia, pp 2080–2128Google Scholar
  18. 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(9):4731–4740CrossRefPubMedPubMedCentralGoogle Scholar
  19. Dimitrova DS, Gilbert DM (1999) The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol Cell 4(6):983–993CrossRefPubMedGoogle Scholar
  20. Direkze S, Laman H (2004) Regulation of growth signalling and cell cycle by Kaposi’s sarcoma-associated herpesvirus genes. Int J Exp Pathol 85(6):305–319CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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(10):8309–8315PubMedPubMedCentralGoogle Scholar
  22. Dourmishev LA, Dourmishev AL, Palmeri D, Schwartz RA, Lukac DM (2003) Molecular genetics of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiol Mol Biol Rev 67(2):175–212. table of contentsCrossRefPubMedPubMedCentralGoogle Scholar
  23. Duus KM, Lentchitsky V, Wagenaar T, Grose C, Webster-Cyriaque J (2004) Wild-type Kaposi’s sarcoma-associated herpesvirus isolated from the oropharynx of immune-competent individuals has tropism for cultured oral epithelial cells. J Virol 78(8):4074–4084CrossRefPubMedPubMedCentralGoogle Scholar
  24. Feldman ER, Kara M, Coleman CB, Grau KR, Oko LM, Krueger BJ, Renne R, van Dyk LF, Tibbetts SA (2014) Virus-encoded microRNAs facilitate gammaherpesvirus latency and pathogenesis in vivo. MBio 5(3):e00981–e00914. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS, Hayward SD (2003) A novel viral mechanism for dysregulation of beta-catenin in Kaposi’s sarcoma-associated herpesvirus latency. Nat Med 9(3):300–306CrossRefPubMedGoogle Scholar
  26. 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(5):1466–1476CrossRefPubMedGoogle Scholar
  27. Gottwein E (2012) Kaposi’s sarcoma-associated herpesvirus microRNAs. Front Microbiol 3:165. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Grundhoff A, Ganem D (2001) Mechanisms governing expression of the v-FLIP gene of Kaposi’s sarcoma-associated herpesvirus. J Virol 75(4):1857–1863CrossRefPubMedPubMedCentralGoogle Scholar
  29. Grundhoff A, Ganem D (2004) Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. J Clin Invest 113(1):124–136CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, Schwartz RA, Seeber S (2002) Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis 2(5):281–292CrossRefPubMedGoogle Scholar
  31. Hu J, Renne R (2005) Characterization of the minimal replicator of Kaposi’s sarcoma-associated herpesvirus latent origin. J Virol 79(4):2637–2642CrossRefPubMedPubMedCentralGoogle Scholar
  32. Hu J, Garber AC, Renne R (2002) The latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus supports latent DNA replication in dividing cells. J Virol 76(22):11677–11687CrossRefPubMedPubMedCentralGoogle Scholar
  33. Jenner RG, Alba MM, Boshoff C, Kellam P (2001) Kaposi’s sarcoma-associated herpesvirus latent and lytic gene expression as revealed by DNA arrays. J Virol 75(2):891–902CrossRefPubMedPubMedCentralGoogle Scholar
  34. Karass M, Grossniklaus E, Seoud T, Jain S, Goldstein DA (2017) Kaposi sarcoma inflammatory cytokine syndrome (KICS): a rare but potentially treatable condition. Oncologist 22(5):623–625. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Klochkov DB, Gavrilov AA, Vassetzky YS, Razin SV (2009) Early replication timing of the chicken alpha-globin gene domain correlates with its open chromatin state in cells of different lineages. Genomics 93(5):481–486. CrossRefPubMedGoogle Scholar
  36. Knipe DM, Lieberman PM, Jung JU, McBride AA, Morris KV, Ott M, Margolis D, Nieto A, Nevels M, Parks RJ, Kristie TM (2013) Snapshots: chromatin control of viral infection. Virology 435(1):141–156. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Koopal S, Furuhjelm JH, Jarviluoma A, Jaamaa S, Pyakurel P, Pussinen C, Wirzenius M, Biberfeld P, Alitalo K, Laiho M, Ojala PM (2007) Viral oncogene-induced DNA damage response is activated in Kaposi sarcoma tumorigenesis. PLoS Pathog 3(9):1348–1360CrossRefPubMedGoogle Scholar
  38. 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(7):3601–3620CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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(12):6585–6594CrossRefPubMedPubMedCentralGoogle Scholar
  40. Lee JS, Li Q, Lee JY, Lee SH, Jeong JH, Lee HR, Chang H, Zhou FC, Gao SJ, Liang C, Jung JU (2009) FLIP-mediated autophagy regulation in cell death control. Nat Cell Biol 11(11):1355–1362. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lei X, Bai Z, Ye F, Huang Y, Gao SJ (2010a) Regulation of herpesvirus lifecycle by viral microRNAs. Virulence 1(5):433–435. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Lei X, Bai Z, Ye F, Xie J, Kim CG, Huang Y, Gao SJ (2010b) Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol 12(2):193–199. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Leidal AM, Cyr DP, Hill RJ, Lee PW, McCormick C (2012) Subversion of autophagy by Kaposi’s sarcoma-associated herpesvirus impairs oncogene-induced senescence. Cell Host Microbe 11(2):167–180. CrossRefPubMedGoogle Scholar
  44. Li M, Lee H, Yoon DW, Albrecht JC, Fleckenstein B, Neipel F, Jung JU (1997) Kaposi’s sarcoma-associated herpesvirus encodes a functional cyclin. J Virol 71(3):1984–1991PubMedPubMedCentralGoogle Scholar
  45. Liang C (2012) Viral FLIPping autophagy for longevity. Cell Host Microbe 11(2):101–103. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Longnecker RM, Kieff E, Cohen JI (2013) In: Knipe DMHPM (ed) Epstein-Barr virus, Fields Virology, vol 2, 6th edn. Lippincott Willamas and Wilkins, Philadelphia, pp 1898–1959Google Scholar
  47. Low W, Harries M, Ye H, Du MQ, Boshoff C, Collins M (2001) Internal ribosome entry site regulates translation of Kaposi’s sarcoma-associated herpesvirus FLICE inhibitory protein. J Virol 75(6):2938–2945CrossRefPubMedPubMedCentralGoogle Scholar
  48. Marshall V, Parks T, Bagni R, Wang CD, Samols MA, Hu J, Wyvil KM, Aleman K, Little RF, Yarchoan R, Renne R, Whitby D (2007) Conservation of virally encoded microRNAs in Kaposi sarcoma--associated herpesvirus in primary effusion lymphoma cell lines and in patients with Kaposi sarcoma or multicentric Castleman disease. J Infect Dis 195(5):645–659CrossRefPubMedGoogle Scholar
  49. Martin JN, Ganem DE, Osmond DH, Page-Shafer KA, Macrae D, Kedes DH (1998) Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med 338(14):948–954CrossRefPubMedGoogle Scholar
  50. Matta H, Mazzacurati L, Schamus S, Yang T, Sun Q, Chaudhary PM (2007a) Kaposi’s sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation. J Biol Chem 282(34):24858–24865CrossRefPubMedGoogle Scholar
  51. Matta H, Mazzacurati L, Schamus S, Yang T, Sun Q, Chaudhary PM (2007b) KSHV oncoprotein K13 bypasses TRAFs and directly interacts with the Ikappa B kinase complex to selectively activate NF-kappa B without JNK activation. J Biol Chem 282:24858–24865CrossRefPubMedGoogle Scholar
  52. McCormick C, Ganem D (2005) The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 307(5710):739–741CrossRefPubMedGoogle Scholar
  53. McCormick C, Ganem D (2006) Phosphorylation and function of the kaposin B direct repeats of Kaposi’s sarcoma-associated herpesvirus. J Virol 80(12):6165–6170CrossRefPubMedPubMedCentralGoogle Scholar
  54. Ohsaki E, Ueda K (2012) Kaposi’s sarcoma-associated herpesvirus genome replication, partitioning, and maintenance in latency. Front Microbiol 3(7).
  55. Ohsaki E, Suzuki T, Karayama M, Ueda K (2009) Accumulation of LANA at nuclear matrix fraction is important for Kaposi’s sarcoma-associated herpesvirus replication in latency. Virus Res 139(1):74–84. CrossRefPubMedGoogle Scholar
  56. Pellett PERB (2013) In: Knipe DMHPM (ed) Herpesviridae, Fields virology, vol 2, 6th edn. Lippincott Williams and Wilkins, Philadelphia, pp 1802–1822Google Scholar
  57. Plancoulaine S, Abel L, van Beveren M, Tregouet DA, Joubert M, Tortevoye P, de The G, Gessain A (2000) Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population. Lancet 356(9235):1062–1065. CrossRefPubMedGoogle Scholar
  58. Rahayu R, Ohsaki E, Omori H, Ueda K (2016) Localization of latency-associated nuclear antigen (LANA) on mitotic chromosomes. Virology 496:51–58. CrossRefPubMedGoogle Scholar
  59. Renne R, Lagunoff M, Zhong W, Ganem D (1996) The size and conformation of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 70(11):8151–8154PubMedPubMedCentralGoogle Scholar
  60. Sadler R, Wu L, Forghani B, Renne R, Zhong W, Herndier B, Ganem D (1999) A complex translational program generates multiple novel proteins from the latently expressed kaposin (K12) locus of Kaposi’s sarcoma-associated herpesvirus. J Virol 73(7):5722–5730PubMedPubMedCentralGoogle Scholar
  61. Sakakibara S, Ueda K, Nishimura K, Do E, Ohsaki E, Okuno T, Yamanishi K (2004) Accumulation of heterochromatin components on the terminal repeat sequence of Kaposi’s sarcoma-associated herpesvirus mediated by the latency-associated nuclear antigen. J Virol 78(14):7299–7310CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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(2):1438–1446PubMedPubMedCentralGoogle Scholar
  63. Schwaiger M, Kohler H, Oakeley EJ, Stadler MB, Schubeler D (2010) Heterochromatin protein 1 (HP1) modulates replication timing of the Drosophila genome. Genome Res 20(6):771–780. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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(4):1276–1280PubMedGoogle Scholar
  65. 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(22):12566–12575CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sun R, Lin SF, Staskus K, Gradoville L, Grogan E, Haase A, Miller G (1999) Kinetics of Kaposi’s sarcoma-associated herpesvirus gene expression. J Virol 73(3):2232–2242PubMedPubMedCentralGoogle Scholar
  67. Sun Q, Tsurimoto T, Juillard F, Li L, Li S, De Leon Vazquez E, Chen S, Kaye K (2014) Kaposi’s sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence. Proc Natl Acad Sci U S A 111(32):11816–11821. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386(6624):517–521CrossRefPubMedGoogle Scholar
  69. 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(1–2):85–94CrossRefPubMedGoogle Scholar
  70. Veettil MV, Bandyopadhyay C, Dutta D, Chandran B (2014) Interaction of KSHV with host cell surface receptors and cell entry. Virus 6(10):4024–4046. CrossRefGoogle Scholar
  71. Verma SC, Robertson ES (2003) Molecular biology and pathogenesis of Kaposi sarcoma-associated herpesvirus. FEMS Microbiol Lett 222(2):155–163CrossRefPubMedGoogle Scholar
  72. 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(5):2243–2256CrossRefPubMedPubMedCentralGoogle Scholar
  73. Verma SC, Lan K, Choudhuri T, Cotter MA, Robertson ES (2007) An autonomous replicating element within the KSHV genome. Cell Host Microbe 2(2):106–118CrossRefPubMedPubMedCentralGoogle Scholar
  74. 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(3):229–241CrossRefPubMedGoogle Scholar
  75. Virgin HW, Wherry EJ, Ahmed R (2009) Redefining chronic viral infection. Cell 138(1):30–50. CrossRefPubMedGoogle Scholar
  76. Wei F, Gan J, Wang C, Zhu C, Cai Q (2016) Cell cycle regulatory functions of the KSHV Oncoprotein LANA. Front Microbiol 7(334).
  77. 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(19):9718–9732. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 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(12):6873–6884. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Division of Virology, Department of Microbiology and ImmunologyOsaka University Graduate School of MedicineOsakaJapan

Personalised recommendations