Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8), is a member of the lymphotropic gammaherpesvirus subfamily and a human oncogenic virus. Since its discovery in AIDS-associated KS tissues by Drs. Yuan Chang and Patrick Moore, much progress has been made in the past two decades. There are four types of KS including classic KS, endemic KS, immunosuppressive therapy-related KS, and AIDS-associated KS. In addition to KS, KSHV is also involved in the development of primary effusion lymphoma (PEL) and certain types of multicentric Castleman’s disease. KSHV manipulates numerous viral proteins to promote the progression of angiogenesis and tumorigenesis. In this chapter, we review the epidemiology and molecular biology of KSHV and the mechanisms underlying KSHV-induced diseases.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Safai B, Good RA (1981) Kaposi’s sarcoma: a review and recent developments. CA Cancer J Clin 31(1):2–12
Friedman-Kien AE (1981) Disseminated Kaposi’s sarcoma syndrome in young homosexual men. J Am Acad Dermatol 5(4):468–471
Wang X et al (2010) Human herpesvirus-8 in northwestern China: epidemiology and characterization among blood donors. Virol J 7:62
Dilnur P et al (2001) Classic type of Kaposi’s sarcoma and human herpesvirus 8 infection in Xinjiang, China. Pathol Int 51(11):845–852
Giraldo G, Beth E, Haguenau F (1972) Herpes-type virus particles in tissue culture of Kaposi’s sarcoma from different geographic regions. J Natl Cancer Inst 49(6):1509–1526
Walter PR et al (1984) Kaposi’s sarcoma: presence of herpes-type virus particles in a tumor specimen. Hum Pathol 15(12):1145–1146
Beral V et al (1990) Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 335(8682):123–128
Chang Y et al (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266(5192):1865–1869
Wu L et al (2000) Three-dimensional structure of the human herpesvirus 8 capsid. J Virol 74(20):9646–9654
Nealon K et al (2001) Lytic replication of Kaposi’s sarcoma-associated herpesvirus results in the formation of multiple capsid species: isolation and molecular characterization of A, B, and C capsids from a gammaherpesvirus. J Virol 75(6):2866–2878
Lo P et al (2003) Three-dimensional localization of pORF65 in Kaposi’s sarcoma-associated herpesvirus capsid. J Virol 77(7):4291–4297
Perkins EM et al (2008) Small capsid protein pORF65 is essential for assembly of Kaposi’s sarcoma-associated herpesvirus capsids. J Virol 82(14):7201–7211
Sathish N, Yuan Y (2010) Functional characterization of Kaposi’s sarcoma-associated herpesvirus small capsid protein by bacterial artificial chromosome-based mutagenesis. Virology 407(2):306–318
Deng B et al (2008) Cryo-electron tomography of Kaposi’s sarcoma-associated herpesvirus capsids reveals dynamic scaffolding structures essential to capsid assembly and maturation. J Struct Biol 161(3):419–427
Deng B et al (2007) Direct visualization of the putative portal in the Kaposi’s sarcoma-associated herpesvirus capsid by cryoelectron tomography. J Virol 81(7):3640–3644
Akula SM et al (2001) Human herpesvirus 8 envelope-associated glycoprotein B interacts with heparan sulfate-like moieties. Virology 284(2):235–249
Baghian A et al (2000) Glycoprotein B of human herpesvirus 8 is a component of the virion in a cleaved form composed of amino- and carboxyl-terminal fragments. Virology 269(1):18–25
Koyano S et al (2003) Glycoproteins M and N of human herpesvirus 8 form a complex and inhibit cell fusion. J Gen Virol 84(Pt 6):1485–1491
Naranatt PP, Akula SM, Chandran B (2002) Characterization of gamma2-human herpesvirus-8 glycoproteins gH and gL. Arch Virol 147(7):1349–1370
Wang FZ et al (2001) Human herpesvirus 8 envelope glycoprotein K8.1A interaction with the target cells involves heparan sulfate. J Virol 75(16):7517–7527
Zhu FX et al (2005) Virion proteins of Kaposi’s sarcoma-associated herpesvirus. J Virol 79(2):800–811
Bechtel JT, Winant RC, Ganem D (2005) Host and viral proteins in the virion of Kaposi’s sarcoma-associated herpesvirus. J Virol 79(8):4952–4964
Sathish N, Wang X, Yuan Y (2012) Tegument proteins of Kaposi’s sarcoma-associated herpesvirus and related gamma-herpesviruses. Front Microbiol 3:98
Vittone V et al (2005) Determination of interactions between tegument proteins of herpes simplex virus type 1. J Virol 79(15):9566–9571
Zhou ZH et al (1999) Visualization of tegument-capsid interactions and DNA in intact herpes simplex virus type 1 virions. J Virol 73(4):3210–3218
Chen DH et al (1999) Three-dimensional visualization of tegument/capsid interactions in the intact human cytomegalovirus. Virology 260(1):10–16
Dai W et al (2008) Unique structures in a tumor herpesvirus revealed by cryo-electron tomography and microscopy. J Struct Biol 161(3):428–438
Dai X et al (2014) Organization of capsid-associated tegument components in Kaposi’s sarcoma-associated herpesvirus. J Virol 88(21):12694–12702
Russo JJ et al (1996) Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A 93(25):14862–14867
Coscoy L (2007) Immune evasion by Kaposi’s sarcoma-associated herpesvirus. Nat Rev Immunol 7(5):391–401
Lagunoff M, Ganem D (1997) The structure and coding organization of the genomic termini of Kaposi’s sarcoma-associated herpesvirus. Virology 236(1):147–154
Moore PS, Chang Y (2001) Molecular virology of Kaposi’s sarcoma-associated herpesvirus. Philos Trans R Soc Lond Ser B Biol Sci 356(1408):499–516
Wen KW, Damania B (2010) Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289(2):140–150
Chandriani S, Xu Y, Ganem D (2010) The lytic transcriptome of Kaposi’s sarcoma-associated herpesvirus reveals extensive transcription of noncoding regions, including regions antisense to important genes. J Virol 84(16):7934–7942
Gottwein E (2012) Kaposi’s sarcoma-associated herpesvirus microRNAs. Front Microbiol 3:165
Sun R et al (1996) Polyadenylated nuclear RNA encoded by Kaposi sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 93(21):11883–11888
Piedade D, Azevedo-Pereira J (2016) The role of microRNAs in the pathogenesis of herpesvirus infection. Virus 8(6):156
Fields BN,KD, Howley PM (2013) Fields virology, 6th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia
Perna AM et al (2000) Antibodies to human herpes virus type 8 (HHV8) in general population and in individuals at risk for sexually transmitted diseases in western Sicily. Int J Epidemiol 29(1):175–179
Viviano E et al (1997) Human herpesvirus type 8 DNA sequences in biological samples of HIV-positive and negative individuals in Sicily. AIDS 11(5):607–612
Whitby D et al (1995) Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi’s sarcoma. Lancet 346(8978):799–802
Mesri EA, Cesarman E, Boshoff C (2010) Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer 10(10):707–719
Moore PS, Chang Y (1995) Detection of herpesvirus-like DNA sequences in Kaposi’s sarcoma in patients with and without HIV infection. N Engl J Med 332(18):1181–1185
Nicholas J et al (1998) Novel organizational features, captured cellular genes, and strain variability within the genome of KSHV/HHV8. J Natl Cancer Inst Monogr 23:79–88
Poole LJ et al (1999) Comparison of genetic variability at multiple loci across the genomes of the major subtypes of Kaposi’s sarcoma-associated herpesvirus reveals evidence for recombination and for two distinct types of open reading frame K15 alleles at the right-hand end. J Virol 73(8):6646–6660
Zong JC et al (1999) High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi’s sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations. J Virol 73(5):4156–4170
Hughes AL, Hughes MA (2007) Nucleotide substitution at the highly polymorphic K1 locus of human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus). Infect Genet Evol 7(1):110–115
Zong J et al (2002) Genotypic analysis at multiple loci across Kaposi’s sarcoma herpesvirus (KSHV) DNA molecules: clustering patterns, novel variants and chimerism. J Clin Virol 23(3):119–148
Ramos da Silva S et al (2011) KSHV genotypes A and C are more frequent in Kaposi sarcoma lesions from Brazilian patients with and without HIV infection, respectively. Cancer Lett 301(1):85–94
Ramos-da-Silva S et al (2006) Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma in Brazil. Braz J Med Biol Res 39(5):573–580
Ouyang X et al (2014) Genotypic analysis of Kaposi’s sarcoma-associated herpesvirus from patients with Kaposi’s sarcoma in Xinjiang, China. Viruses 6(12):4800–4810
Nsubuga MM et al (2008) Human herpesvirus 8 load and progression of AIDS-related Kaposi sarcoma lesions. Cancer Lett 263(2):182–188
Gogineni E et al (2013) Quantitative determinations of anti-Kaposi sarcoma-associated herpesvirus antibody levels in men who have sex with men. Diagn Microbiol Infect Dis 76(1):56–60
Hladik W et al (2006) Transmission of human herpesvirus 8 by blood transfusion. N Engl J Med 355(13):1331–1338
Aluigi MG et al (1996) KSHV sequences in biopsies and cultured spindle cells of epidemic, iatrogenic and Mediterranean forms of Kaposi’s sarcoma. Res Virol 147(5):267–275
Kasolo FC, Mpabalwani E, Gompels UA (1997) Infection with AIDS-related herpesviruses in human immunodeficiency virus-negative infants and endemic childhood Kaposi’s sarcoma in Africa. J Gen Virol 78(Pt 4):847–855
Minhas V, Wood C (2014) Epidemiology and transmission of Kaposi’s sarcoma-associated herpesvirus. Virus 6(11):4178–4194
Olsen SJ et al (1998) Increasing Kaposi’s sarcoma-associated herpesvirus seroprevalence with age in a highly Kaposi’s sarcoma endemic region, Zambia in 1985. AIDS 12(14):1921–1925
Cao Y et al (2014) High prevalence of early childhood infection by Kaposi’s sarcoma-associated herpesvirus in a minority population in China. Clin Microbiol Infect 20(5):475–481
Plancoulaine S et al (2000) Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population. Lancet 356(9235):1062–1065
Butler LM et al (2011) Human herpesvirus 8 infection in children and adults in a population-based study in rural Uganda. J Infect Dis 203(5):625–634
Brayfield BP et al (2004) Distribution of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 in maternal saliva and breast milk in Zambia: implications for transmission. J Infect Dis 189(12):2260–2270
Marcelin AG et al (2004) Quantification of Kaposi’s sarcoma-associated herpesvirus in blood, oral mucosa, and saliva in patients with Kaposi’s sarcoma. AIDS Res Hum Retrovir 20(7):704–708
Ruocco E et al (2013) Kaposi’s sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies. Clin Dermatol 31(4):413–422
He F et al (2007) Human herpesvirus 8: seroprevalence and correlates in tumor patients from Xinjiang, China. J Med Virol 79(2):161–166
Geraminejad P et al (2002) Kaposi’s sarcoma and other manifestations of human herpesvirus 8. J Am Acad Dermatol 47(5):641–655. quiz 656-8
Xu Y, Ganem D (2007) Induction of chemokine production by latent Kaposi’s sarcoma-associated herpesvirus infection of endothelial cells. J Gen Virol 88(Pt 1):46–50
Gandhi M, Greenblatt RM (2002) Human herpesvirus 8, Kaposi’s sarcoma, and associated conditions. Clin Lab Med 22(4):883–910
Said JW et al (1996) Primary effusion lymphoma in women: report of two cases of Kaposi’s sarcoma herpes virus-associated effusion-based lymphoma in human immunodeficiency virus-negative women. Blood 88(8):3124–3128
Ascoli V et al (1999) Human herpesvirus-8 in lymphomatous and nonlymphomatous body cavity effusions developing in Kaposi’s sarcoma and multicentric Castleman’s disease. Ann Diagn Pathol 3(6):357–363
Soulier J et al (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 86(4):1276–1280
Katano H et al (2000) Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi’s sarcoma, and multicentric Castleman’s disease. Virology 269(2):335–344
Bechtel JT et al (2003) Host range of Kaposi’s sarcoma-associated herpesvirus in cultured cells. J Virol 77(11):6474–6481
Jarousse N, Chandran B, Coscoy L (2008) Lack of heparan sulfate expression in B-cell lines: implications for Kaposi’s sarcoma-associated herpesvirus and murine gammaherpesvirus 68 infections. J Virol 82(24):12591–12597
Chandran B (2010) Early events in Kaposi’s sarcoma-associated herpesvirus infection of target cells. J Virol 84(5):2188–2199
Inoue N et al (2003) Characterization of entry mechanisms of human herpesvirus 8 by using an Rta-dependent reporter cell line. J Virol 77(14):8147–8152
Rappocciolo G et al (2008) Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN. J Virol 82(10):4793–4806
Raghu H et al (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(10):4895–4911
Akula SM et al (2003) Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) infection of human fibroblast cells occurs through endocytosis. J Virol 77(14):7978–7990
Liao W et al (2003) Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 transcriptional activator Rta is an oligomeric DNA-binding protein that interacts with tandem arrays of phased A/T-trinucleotide motifs. J Virol 77(17):9399–9411
Neipel F, Albrecht JC, Fleckenstein B (1997) Cell-homologous genes in the Kaposi’s sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J Virol 71(6):4187–4192
Cesarman E et al (1996) Kaposi’s sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi’s sarcoma and malignant lymphoma. J Virol 70(11):8218–8223
Akula SM et al (2001) Human herpesvirus 8 interaction with target cells involves heparan sulfate. Virology 282(2):245–255
Wang FZ et al (2003) Human herpesvirus 8 envelope glycoprotein B mediates cell adhesion via its RGD sequence. J Virol 77(5):3131–3147
Akula SM et al (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(3):407–419
Rappocciolo G et al (2006) DC-SIGN is a receptor for human herpesvirus 8 on dendritic cells and macrophages. J Immunol 176(3):1741–1749
Kaleeba JA, Berger EA (2006) Kaposi’s sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT. Science 311(5769):1921–1924
Hahn AS et al (2012) The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus. Nat Med 18(6):961–966
Giancotti FG (2000) Complexity and specificity of integrin signalling. Nat Cell Biol 2(1):E13–E14
Sharma-Walia N et al (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(8):4207–4223
Raghu H et al (2007) Lipid rafts of primary endothelial cells are essential for Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8-induced phosphatidylinositol 3-kinase and RhoA-GTPases critical for microtubule dynamics and nuclear delivery of viral DNA but dispensable for binding and entry. J Virol 81(15):7941–7959
Naranatt PP et al (2003) Kaposi’s sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol 77(2):1524–1539
Veettil MV et al (2006) RhoA-GTPase facilitates entry of Kaposi’s sarcoma-associated herpesvirus into adherent target cells in a Src-dependent manner. J Virol 80(23):11432–11446
Naranatt PP et al (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(2):1191–1206
Hurley JH, Hanson PI (2010) Membrane budding and scission by the ESCRT machinery: it’s all in the neck. Nat Rev Mol Cell Biol 11(8):556–566
Sharma-Walia N et al (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(16):10308–10329
Cheng F et al (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(18):9262–9280
Sadagopan S et al (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(8):3949–3968
Zhao Q et al (2015) Kaposi’s sarcoma-associated herpesvirus-encoded replication and transcription activator impairs innate immunity via ubiquitin-mediated degradation of myeloid differentiation factor 88. J Virol 89(1):415–427
Cai Q et al (2010) Molecular biology of Kaposi’s sarcoma-associated herpesvirus and related oncogenesis. Adv Virus Res 78:87–142
Kedes DH et al (1997) Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi’s sarcoma-associated herpesvirus. J Clin Invest 100(10):2606–2610
Cai X et al (2005) Kaposi’s sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci U S A 102(15):5570–5575
Kellam P et al (1997) Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome. J Hum Virol 1(1):19–29
Rainbow L et al (1997) The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen. J Virol 71(8):5915–5921
Ballestas ME, Chatis PA, Kaye KM (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284(5414):641–644
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):254–264
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):11677–11687
Lan K et al (2005) Induction of Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen by the lytic transactivator RTA: a novel mechanism for establishment of latency. J Virol 79(12):7453–7465
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(10):1121–1127
Lim C et al (2000) Latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. J Gen Virol 81(Pt 11):2645–2652
Chang Y et al (1996) Cyclin encoded by KS herpesvirus. Nature 382(6590):410
Li M et al (1997) Kaposi’s sarcoma-associated herpesvirus encodes a functional cyclin. J Virol 71(3):1984–1991
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):305–319
Sarek G et al (2010) Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV latency. PLoS Pathog 6(3):e1000818
Ojala PM et al (1999) Kaposi’s sarcoma-associated herpesvirus-encoded v-cyclin triggers apoptosis in cells with high levels of cyclin-dependent kinase 6. Cancer Res 59(19):4984–4989
Ojala PM et al (2000) The apoptotic v-cyclin-CDK6 complex phosphorylates and inactivates Bcl-2. Nat Cell Biol 2(11):819–825
Liang X et al (2011) Murine gamma-herpesvirus immortalization of fetal liver-derived B cells requires both the viral cyclin D homolog and latency-associated nuclear antigen. PLoS Pathog 7(9):e1002220
Ye FC et al (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(9):4235–4249
Guasparri I, Keller SA, Cesarman E (2004) KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 199(7):993–1003
Israel A (2010) The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2(3):a000158
Field N et al (2003) KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci 116(Pt 18):3721–3728
Brown HJ et al (2003) NF-kappaB inhibits gammaherpesvirus lytic replication. J Virol 77(15):8532–8540
Guasparri I, Wu H, Cesarman E (2006) The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. EMBO Rep 7(1):114–119
McCormick C, Ganem D (2005) The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 307(5710):739–741
O’Hara AJ et al (2009) Pre-micro RNA signatures delineate stages of endothelial cell transformation in Kaposi sarcoma. PLoS Pathog 5(4):e1000389
O’Hara AJ et al (2009) Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma. Blood 113(23):5938–5941
Liang D, Lin X, Lan K (2011) Looking at Kaposi’s sarcoma-associated herpesvirus-host interactions from a microRNA viewpoint. Front Microbiol 2:271
Lin X et al (2012) MicroRNAs and unusual small RNAs discovered in Kaposi’s sarcoma-associated herpesvirus virions. J Virol 86(23):12717–12730
Liu Y et al (2012) Kaposi’s sarcoma-associated herpesvirus-encoded microRNA miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5. J Virol 86(3):1372–1381
Lin X et al (2011) miR-K12-7-5p encoded by Kaposi’s sarcoma-associated herpesvirus stabilizes the latent state by targeting viral ORF50/RTA. PLoS One 6(1):e16224
Suffert G et al (2011) Kaposi’s sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis. PLoS Pathog 7(12):e1002405
Hansen A et al (2010) KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming. Genes Dev 24(2):195–205
Qin Z et al (2012) KSHV-encoded MicroRNAs: lessons for viral cancer pathogenesis and emerging concepts. Int J Cell Biol 2012:603961
Liang D et al (2011) A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKepsilon. Cell Res 21(5):793–806
Krishnan HH et al (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):3601–3620
Renne R et al (1996) Lytic growth of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 2(3):342–346
Jenner RG et al (2001) Kaposi’s sarcoma-associated herpesvirus latent and lytic gene expression as revealed by DNA arrays. J Virol 75(2):891–902
Wang SE et al (2003) CCAAT/enhancer-binding protein-alpha is induced during the early stages of Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic cycle reactivation and together with the KSHV replication and transcription activator (RTA) cooperatively stimulates the viral RTA, MTA, and PAN promoters. J Virol 77(17):9590–9612
Deng H, Young A, Sun R (2000) Auto-activation of the rta gene of human herpesvirus-8/Kaposi’s sarcoma-associated herpesvirus. J Gen Virol 81(Pt 12):3043–3048
Song MJ, Deng H, Sun R (2003) Comparative study of regulation of RTA-responsive genes in Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8. J Virol 77(17):9451–9462
Wang Y et al (2006) Kaposi’s sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: dual role of replication and transcription activator. J Virol 80(24):12171–12186
Chen J et al (2009) Genome-wide identification of binding sites for Kaposi’s sarcoma-associated herpesvirus lytic switch protein. RTA Virology 386(2):290–302
Liang Y, Ganem D (2003) Lytic but not latent infection by Kaposi’s sarcoma-associated herpesvirus requires host CSL protein, the mediator of notch signaling. Proc Natl Acad Sci U S A 100(14):8490–8495
Li S et al (2016) Fine-tuning of the Kaposi’s sarcoma-associated herpesvirus life cycle in neighboring cells through the RTA-JAG1-notch pathway. PLoS Pathog 12(10):e1005900
Dittmer DP, Damania B (2013) Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)--an update. Curr Opin Virol 3(3):238–244
Li Q et al (2008) Genetic disruption of KSHV major latent nuclear antigen LANA enhances viral lytic transcriptional program. Virology 379(2):234–244
Yoo J et al (2012) Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus. PLoS Pathog 8(6):e1002770
Cheng F et al (2011) KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition. Cell Host Microbe 10(6):577–590
Staskus KA et al (1997) Kaposi’s sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 71(1):715–719
Boshoff C et al (1995) Kaposi’s sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med 1(12):1274–1278
Jussila L et al (1998) Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res 58(8):1599–1604
Wang HW et al (2004) Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36(7):687–693
Kahn HJ, Bailey D, Marks A (2002) Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol 15(4):434–440
Pyakurel P et al (2006) Lymphatic and vascular origin of Kaposi’s sarcoma spindle cells during tumor development. Int J Cancer 119(6):1262–1267
Hong YK et al (2004) Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36(7):683–685
Carroll PA, Brazeau E, Lagunoff M (2004) Kaposi’s sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology 328(1):7–18
Kaaya EE et al (1995) Heterogeneity of spindle cells in Kaposi’s sarcoma: comparison of cells in lesions and in culture. J Acquir Immune Defic Syndr Hum Retrovirol 10(3):295–305
Ciufo DM et al (2001) Spindle cell conversion by Kaposi’s sarcoma-associated herpesvirus: formation of colonies and plaques with mixed lytic and latent gene expression in infected primary dermal microvascular endothelial cell cultures. J Virol 75(12):5614–5626
Abere B, Schulz TF (2016) KSHV non-structural membrane proteins involved in the activation of intracellular signaling pathways and the pathogenesis of Kaposi’s sarcoma. Curr Opin Virol 20:11–19
Abboud ER et al (2013) Kaposi sarcoma-associated herpesvirus g protein-coupled receptor enhances endothelial cell survival in part by upregulation of bcl-2. Ochsner J 13(1):66–75
Sadagopan S et al (2009) Kaposi’s sarcoma-associated herpesvirus upregulates angiogenin during infection of human dermal microvascular endothelial cells, which induces 45S rRNA synthesis, antiapoptosis, cell proliferation, migration, and angiogenesis. J Virol 83(7):3342–3364
Raggo C et al (2005) Novel cellular genes essential for transformation of endothelial cells by Kaposi’s sarcoma-associated herpesvirus. Cancer Res 65(12):5084–5095
Flore O et al (1998) Transformation of primary human endothelial cells by Kaposi’s sarcoma-associated herpesvirus. Nature 394(6693):588–592
Lagunoff M et al (2002) De novo infection and serial transmission of Kaposi’s sarcoma-associated herpesvirus in cultured endothelial cells. J Virol 76(5):2440–2448
Cancian L, Hansen A, Boshoff C (2013) Cellular origin of Kaposi’s sarcoma and Kaposi’s sarcoma-associated herpesvirus-induced cell reprogramming. Trends Cell Biol 23(9):421–432
Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8(6):464–478
Salahuddin SZ et al (1988) Angiogenic properties of Kaposi’s sarcoma-derived cells after long-term culture in vitro. Science 242(4877):430–433
Ensoli B et al (1989) AIDS-Kaposi’s sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science 243(4888):223–226
Samaniego F et al (1995) Inflammatory cytokines induce AIDS-Kaposi’s sarcoma-derived spindle cells to produce and release basic fibroblast growth factor and enhance Kaposi’s sarcoma-like lesion formation in nude mice. J Immunol 154(7):3582–3592
Samaniego F et al (1997) Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi’s sarcoma-like lesions in nude mice. J Immunol 158(4):1887–1894
Mansouri M et al (2008) Remodeling of endothelial adherens junctions by Kaposi’s sarcoma-associated herpesvirus. J Virol 82(19):9615–9628
Qian LW et al (2008) Kaposi’s sarcoma-associated herpesvirus disrupts adherens junctions and increases endothelial permeability by inducing degradation of VE-cadherin. J Virol 82(23):11902–11912
Wang L, Damania B (2008) Kaposi’s sarcoma-associated herpesvirus confers a survival advantage to endothelial cells. Cancer Res 68(12):4640–4648
DiMaio TA, Gutierrez KD, Lagunoff M (2011) Latent KSHV infection of endothelial cells induces integrin beta3 to activate angiogenic phenotypes. PLoS Pathog 7(12):e1002424
Gasperini P et al (2012) Kaposi sarcoma herpesvirus promotes endothelial-to-mesenchymal transition through notch-dependent signaling. Cancer Res 72(5):1157–1169
Qian LW et al (2007) Kaposi’s sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases. J Virol 81(13):7001–7010
Watanabe T et al (2003) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen prolongs the life span of primary human umbilical vein endothelial cells. J Virol 77(11):6188–6196
Murakami Y et al (2006) Ets-1-dependent expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus through interaction with Daxx. J Biol Chem 281(38):28113–28121
He M et al (2012) Cancer angiogenesis induced by Kaposi sarcoma-associated herpesvirus is mediated by EZH2. Cancer Res 72(14):3582–3592
Wang X et al (2014) Latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus promotes angiogenesis through targeting notch signaling effector Hey1. Cancer Res 74(7):2026–2037
Bais C et al (1998) G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391(6662):86–89
Sodhi A et al (2000) The Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res 60(17):4873–4880
Aoki Y et al (1999) Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93(12):4034–4043
Vart RJ et al (2007) Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res 67(9):4042–4051
Xie J et al (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(24):15027–15037
Felcht M et al (2012) Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest 122(6):1991–2005
Wang L et al (2004) The Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors. Cancer Res 64(8):2774–2781
Bala K et al (2012) Kaposi’s sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathog 8(9):e1002927
Liu C et al (2001) Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects. J Virol 75(22):10933–10940
Cai Q et al (2007) A potential alpha-helix motif in the amino terminus of LANA encoded by Kaposi’s sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1alpha in normoxia. J Virol 81(19):10413–10423
Ema M et al (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 94(9):4273–4278
Brown LF et al (2000) Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi’s sarcoma and cutaneous angiosarcoma. Am J Pathol 156(6):2179–2183
Giffin L et al (2014) Modulation of Kaposi’s sarcoma-associated herpesvirus interleukin-6 function by hypoxia-upregulated protein 1. J Virol 88(16):9429–9441
Choi YB, Nicholas J (2010) Induction of angiogenic chemokine CCL2 by human herpesvirus 8 chemokine receptor. Virology 397(2):369–378
Paul AG, Chandran B, Sharma-Walia N (2013) Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi’s sarcoma-associated herpes virus associated malignancies. Transl Res 162(2):77–92
Cherqui S et al (2007) Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo. Mol Ther 15(7):1264–1272
Stine JT et al (2000) KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood 95(4):1151–1157
Bussey KA et al (2014) The gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus and murine gammaherpesvirus 68 modulate the toll-like receptor-induced proinflammatory cytokine response. J Virol 88(16):9245–9259
Ahmad H et al (2011) Kaposi sarcoma-associated herpesvirus degrades cellular toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF). J Biol Chem 286(10):7865–7872
Jacobs SR et al (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(2):798–806
Gregory SM et al (2011) Discovery of a viral NLR homolog that inhibits the inflammasome. Science 331(6015):330–334
Roy A et al (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(19):8822–8841
Singh VV et al (2013) Kaposi’s sarcoma-associated herpesvirus latency in endothelial and B cells activates gamma interferon-inducible protein 16-mediated inflammasomes. J Virol 87(8):4417–4431
West JA et al (2014) An important role for mitochondrial antiviral signaling protein in the Kaposi’s sarcoma-associated herpesvirus life cycle. J Virol 88(10):5778–5787
Inn KS et al (2011) Inhibition of RIG-I-mediated signaling by Kaposi’s sarcoma-associated herpesvirus-encoded deubiquitinase ORF64. J Virol 85(20):10899–10904
Ma Z et al (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A 112(31):E4306–E4315
Wu JJ et al (2015) Inhibition of cGAS DNA sensing by a herpesvirus Virion protein. Cell Host Microbe 18(3):333–344
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Hu H et al (2011) Proteomics revisits the cancer metabolome. Expert Rev Proteomics 8(4):505–533
Yogev O et al (2014) Kaposi’s sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells. PLoS Pathog 10(9):e1004400
Ma T et al (2015) KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis 18(4):477–488
Zhu Y et al (2016) An oncogenic virus promotes cell survival and cellular transformation by suppressing glycolysis. PLoS Pathog 12(5):e1005648
Ye F et al (2016) High glucose induces reactivation of latent Kaposi’s sarcoma-associated herpesvirus. J Virol 90:9654–9663
Sanchez EL et al (2015) Latent KSHV infected endothelial cells are glutamine addicted and require Glutaminolysis for survival. PLoS Pathog 11(7):e1005052
Delgado T et al (2012) Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS Pathog 8(8):e1002866
Borah S, Verma SC, Robertson ES (2004) ORF73 of herpesvirus saimiri, a viral homolog of Kaposi’s sarcoma-associated herpesvirus, modulates the two cellular tumor suppressor proteins p53 and pRb. J Virol 78(19):10336–10347
Cai QL et al (2006) EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog 2(10):e116
Cai Q et al (2012) Kaposi’s sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation. PLoS Pathog 8(3):e1002566
Shin YC et al (2006) Inhibition of the ATM/p53 signal transduction pathway by Kaposi’s sarcoma-associated herpesvirus interferon regulatory factor 1. J Virol 80(5):2257–2266
Baresova P et al (2014) p53 tumor suppressor protein stability and transcriptional activity are targeted by Kaposi’s sarcoma-associated herpesvirus-encoded viral interferon regulatory factor 3. Mol Cell Biol 34(3):386–399
Chang PC, Li M (2008) Kaposi’s sarcoma-associated herpesvirus K-cyclin interacts with Cdk9 and stimulates Cdk9-mediated phosphorylation of p53 tumor suppressor. J Virol 82(1):278–290
Laura MV et al (2015) KSHV latent protein LANA2 inhibits sumo2 modification of p53. Cell Cycle 14(2):277–282
Chudasama P et al (2015) Structural proteins of Kaposi’s sarcoma-associated herpesvirus antagonize p53-mediated apoptosis. Oncogene 34(5):639–649
Lee HR et al (2009) Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor 4 targets MDM2 to deregulate the p53 tumor suppressor pathway. J Virol 83(13):6739–6747
Lan K et al (2007) Kaposi’s sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein. Proc Natl Acad Sci U S A 104(41):16287–16292
Di Bartolo DL et al (2008) KSHV LANA inhibits TGF-beta signaling through epigenetic silencing of the TGF-beta type II receptor. Blood 111(9):4731–4740
Liang D et al (2014) Oncogenic herpesvirus KSHV Hijacks BMP-Smad1-Id signaling to promote tumorigenesis. PLoS Pathog 10(7):e1004253
Cannon ML, Cesarman E (2004) The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells. Oncogene 23(2):514–523
Sodhi A et al (2006) The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10(2):133–143
Guo HG et al (2004) Tumorigenesis by human herpesvirus 8 vGPCR is accelerated by human immunodeficiency virus type 1 Tat. J Virol 78(17):9336–9342
Uldrick TS et al (2012) Phase II study of bevacizumab in patients with HIV-associated Kaposi’s sarcoma receiving antiretroviral therapy. J Clin Oncol 30(13):1476–1483
Dittmer DP, Damania B (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126(9):3165–3175
Krown SE et al (2012) Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium study. J Acquir Immune Defic Syndr 59(5):447–454
Stallone G et al (2005) Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352(13):1317–1323
Acknowledgments
This work was supported by grants from the Natural Science Foundation for Distinguished Young Scholar (81425017), the Ministry of Science and Technology of China (2016YFA0502100), the Key Project of the National Natural Science Foundation of China (81230037), and the National Institutes of Health (1R01AI116442) to Ke Lan.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Li, S., Bai, L., Dong, J., Sun, R., Lan, K. (2017). Kaposi’s Sarcoma-Associated Herpesvirus: Epidemiology and Molecular Biology. In: Cai, Q., Yuan, Z., Lan, K. (eds) Infectious Agents Associated Cancers: Epidemiology and Molecular Biology. Advances in Experimental Medicine and Biology, vol 1018. Springer, Singapore. https://doi.org/10.1007/978-981-10-5765-6_7
Download citation
DOI: https://doi.org/10.1007/978-981-10-5765-6_7
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-10-5764-9
Online ISBN: 978-981-10-5765-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)