Analysis of the ORFK1 hypervariable regions reveal distinct HHV-8 clustering in Kaposi’s sarcoma and non-Kaposi’s cases

Journal of Experimental & Clinical Cancer Research

Fabrizio Ensoli¹  Massimo Ciccozzi²  Antonio Cristaudo⁶  Antonella Vento¹  Isabella Sperduti⁴  Carlo Cota³  Ilaria Lesnoni La Parola⁵  Carmela Ferraro⁵  Francesca Farchi⁷  Eleonora Cella⁷  Valentina Bordignon¹  Giovanna D’Agosto¹  Massimo Giuliani⁶  Alessandra Latini⁶  Alessandra Lo Presti⁷  Marta Giovanetti⁷  Elisabetta Trento¹  Paola Cordiali-Fei¹ 

[1] Clinical Pathology and Microbiology, San Gallicano Dermatology Institute, Via Elio Chianesi 53, Rome, 00144, Italy;University of Biomedical Campus, Via Álvaro del Portillo, 200, Rome, 00128, Italy;Dermopathology, San Gallicano Dermatology Institute, Via Elio Chianesi 53, Rome, 00144, Italy;Epidemiology, Regina Elena Cancer Institute, Via Elio Chianesi 53, Rome, 00144, Italy;Clinical Dermatology, San Gallicano Dermatology Institute, Via Elio Chianesi 53, Rome, 00144, Italy;Infective Dermatology, San Gallicano Dermatology Institute, Via Elio Chianesi 53, Rome, 00144, Italy;Department of Infectious Parasitic and Immunomediated Diseases, National Institute of Health, Viale Regina Elena 299, Rome, 00161, Italy

关键词: Selective pressure;    HHV-8 variants;    Phylogenesis;    Kaposi’s sarcoma;    HHV-8;   

Others  :  1133650
DOI  :  10.1186/s13046-014-0119-0

 received in 2014-12-11, accepted in 2014-12-29,  发布年份 2015

【 摘 要 】

Background

Classical Kaposi’s Sarcoma (cKS) is a rare vascular tumor, which develops in subjects infected with Human Herpesvirus-8 (HHV-8). Beside the host predisposing factors, viral genetic variants might possibly be related to disease development. The aim of this study was to identify HHV-8 variants in patients with cKS or in HHV-8 infected subjects either asymptomatic or with cKS-unrelated cutaneous lymphoproliferative disorders.

Methods

The VR1 and VR2 regions of the ORF K1 sequence were analyzed in samples (peripheral blood and/or lesional tissue) collected between 2000 and 2010 from 27 subjects with HHV-8 infection, established by the presence of anti-HHV-8 antibodies. On the basis of viral genotyping, a phylogenetic analysis and a time-scaled evaluation were performed.

Results

Two main clades of HHV-8, corresponding to A and C subtypes, were identified. Moreover, for each subtype, two main clusters were found distinctively associated to cKS or non-cKS subjects. Selective pressure analysis showed twelve sites of the K1 coding gene (VR1 and VR2 regions) under positive selective pressure and one site under negative pressure.

Conclusion

Thus, present data suggest that HHV-8 genetic variants may influence the susceptibility to cKS in individuals with HHV-8 infection.

【 授权许可】

   
2015 Cordiali-Fei et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Ablashi DV, Chatlynne LG, Whitman JE, Cesarman E: Spectrum of Kaposi’s sarcoma-associated herpesvirus, or human herpesvirus 8, diseases. Clin Microbiology Rev 2002, 15:439-64.
• [2]Giffin L, Damania B: KSHV: pathway to tumorigenesis and persistent infection. Adv Virus Res 2014, 88:111-59.
• [3]Valdarchi C, Serraino D, Cordiali Fei P, Castilletti C, Trento E, Farchi F, et al.: Demographic indicators and risk of infection with human herpesvirus type 8 in central italy. Infection 2007, 35:22-5.
• [4]Tamburro KM, Yang D, Poisson J, Fedoriw Y, Roy D, Lucas A, et al.: Vironome of kaposi sarcoma associated herpesvirus-inflammatory cytokine syndrome in an AIDS patient reveals co-infection of human herpesvirus 8 and human herpesvirus 6A. Virology 2012, 433:220-5.
• [5]Polizzotto MN, Uldrick TS, Hu D, Yarchoan R: Clinical manifestations of kaposi sarcoma herpesvirus lytic activation: multicentric castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol 2012, 3:73.
• [6]Trento E, Castilletti C, Ferraro C, Lesnoni La Parola I, Mussi A, Muscardin L, et al.: Human herpesvirus 8 infection in patients with cutaneous lymphoproliferative diseases. Arch Dermatol 2005, 141:1235-42.
• [7]Kreuter A, Bischoff S, Skrygan M, Wieland U, Brockmeyer NH, Stucker M, et al.: High association of human herpesvirus 8 in large-plaque parapsoriasis and mycosis fungoides. Arch Dermatol 2008, 144:1011-6.
• [8]Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, et al.: Defining early mycosis fungoides. J Am Acad Dermatol 2005, 53:1053-63.
• [9]Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al.: WHO-EORTC classification for cutaneous lymphomas. Blood 2005, 105:3768-85.
• [10]Rohner E, Wyss N, Trelle S, Mbulaiteye SM, Egger M, Novak U, et al.: HHV-8 seroprevalence: a global view. Syst Rev 2014, 3:11-8. BioMed Central Full Text
• [11]Brown EE, Whitby D, Vitale F, Marshall V, Mbisa G, Gamache C, et al.: Virologic, hematologic, and immunologic risk factors for classic Kaposi sarcoma. Cancer 2006, 107:2282-90.
• [12]Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P: Biology of Kaposi’s sarcoma. Eur J Cancer 2001, 37:1251-69.
• [13]Taylor GS, Blackbourn DJ: Infectious agents in human cancers: Lessons in immunity and immunomodulation from gammaherpesviruses EBV and KSHV. Cancer Lett 2011, 305:263-78.
• [14]O’Brien TR, Kedes D, Ganem D, Macrae DR, Rosenberg PS, Molden J, et al.: Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi’s sarcoma. J Infect Dis 1999, 180:1010-7.
• [15]da Silva SR, de Oliveira DE: HIV, EBV and KSHV: viral cooperation in the pathogenesis of human malignancies. Cancer Lett 2011, 305:175-85.
• [16]Spadavecchia S, Gonzalez-Lopez O, Carroll KD, Palmeri D, Lukac DM: 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 2010, 84:10488-500.
• [17]Cordiali-Fei P, Latini A, Trento E, Zampatti S, Ferraresi V, Cota C, Volpi S, D’agosto G, Bordignon V, Giardina E, Di Carlo A, Cristaudo A, Ensoli F: Familial Kaposi’s Sarcoma in HHV8 infected subjects presenting the G-174C allele of the IL-6 promoter: a possible role for EBV? Eur J Dermatol 2014, 24:503-04.
• [18]Brown EE, Fallin D, Ruczinski I, Hutchinson A, Staats B, Vitale F, et al.: Associations of classic kaposi sarcoma with common variants in genes that modulate host immunity. Cancer Epidemiol Biomarkers Prev 2006, 15:926-34.
• [19]Gazouli M, Zavos G, Papaconstantinou I, Lukas JC, Zografidis A, Boletis J, et al.: The interleukin-6 174 promoter polymorphism is associated with a risk of development of kaposi’s sarcoma in renal transplant recipients. Anticancer Res 2004, 24:1311-4.
• [20]Tornesello ML, Buonaguro L, Cristillo M, Biryahwaho B, Downing R, Hatzakis A, et al.: MDM2 and CDKN1A gene polymorphisms and risk of kaposi’s sarcoma in african and caucasian patients. Biomarkers 2011, 16:42-50.
• [21]Speck SH, Ganem D: Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe 2010, 8:100-15.
• [22]Gonnella R, Santarelli R, Farina A, Granato M, D’Orazi G, Faggioni A, et al.: Kaposi Sarcoma Associated Herpervirus (KSHV) induces AKT hyperphosphorilation, bortezomid-resistance and Glut-1 plasma membrane exposure in THP-1 monocytic cell line. J Exp Clin Cancer Res 2013, 32:79-86. BioMed Central Full Text
• [23]Jham BC, Montaner SJ: The Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene. Cell Biochem 2010, 110:1-9.
• [24]Jham BC, Ma T, Hu J, Chaisuparat R, Friedman ER, Pandolfi PP, et al.: Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi’s sarcoma. PLoS One 2011, 29:e19103.
• [25]Liang D, Hu H, Li S, Dong J, Wang X, Wang Y, et al.: Oncogenic Herpesvirus KSHV Hijacks BMP-Smad1-Id Signaling to Promote Tumorigenesis. PLoS Pathog 2014, 10:e1004253.
• [26]Tomkowicz B, Singh SP, Lai D, Singh A, Mahalingham S, Joseph J, et al.: Mutational analysis reveals an essential role for the LXXLL motif in the transformation function of the human herpesvirus-8 oncoprotein, kaposin. DNA Cell Biol 2005, 24:10-20.
• [27]Lagunoff M, Lukac DM, Ganem D: Immunoreceptor tyrosine-based activation motif-dependent signaling by Kaposi’s sarcoma-associated herpesvirus K1 protein: effects on lytic viral replication. J Virol 2001, 75:5891-8.
• [28]Tomlinson CC, Damania B: Critical role for endocytosis in the regulation of signaling by the Kaposi’s sarcoma-associated herpesvirus K1 protein. J Virol 2008, 82:6514-23.
• [29]Wang L, Dittmer DP, Tomlinson CC, Fakhari FD, Damania B: Immortalization of primary endothelial cells by the K1 protein of Kaposi’s sarcoma-associated herpesvirus. Cancer Res 2006, 66:3658-66.
• [30]Wang L, Wakisaka N, Tomlinson CC, DeWire SM, Krall S, Pagano JS, et al.: The Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors. Cancer Res 2004, 64:2774-81.
• [31]Roy D, Sin SH, Lucas A, Venkataramanan R, Wang L, Eason A, et al.: mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Res 2013, 73:2235-46.
• [32]Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG: Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol 2012, 181:1895-9.
• [33]Zong JC, Ciufo DM, Alcendor DJ, Wan X, Nicholas J, Browning PJ, et al.: 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 1999, 73:4156-70.
• [34]Tornesello ML, Biryahwaho B, Downing R, Hatzakis A, Alessi E, Cusini M, et al.: Human herpesvirus type 8 variants circulating in europe, africa and north america in classic, endemic and epidemic kaposi’s sarcoma lesions during pre-AIDS and AIDS era. Virology 2010, 398:280-9.
• [35]Biggar RJ, Whitby D, Marshall V, Linhares AC, Black F: Human herpesvirus 8 in brazilian amerindians: A hyperendemic population with a new subtype. J Infect Dis 2000, 181:1562-8.
• [36]Kasolo C, Monze M, Obel N, Anderson RA, French C, Gompels UA: Sequence analyses of human herpesvirus-8 strains from both African human immunodeficiency virus-negative and -positive childhood endemic Kaposi’s sarcoma show a close relationship with strains identified in febrile children and high variation in the K1 glycoprotein. Gen Virol 1998, 79:3055-65.
• [37]Betsem E, Cassar O, Afonso PV, Fontanet A, Froment A, Gessain A: Epidemiology and genetic variability of HHV-8/KSHV in Pygmy and Bantu populations in Cameroon. PLoS Negl Trop Dis 2014, 8:e2851.
• [38]Mancuso R, Biffi R, Valli M, Bellinvia M, Tourlaki A, Ferrucci S, et al.: HHV8 a subtype is associated with rapidly evolving classic Kaposi’s sarcoma. J Med Virol 2008, 80:2153-60.
• [39]Zong J, Ciufo DM, Viscidi R, Alagiozoglou L, Tyring S, Rady P, et al.: Genotypic analysis at multiple loci across Kaposi’s sarcoma herpesvirus (KSHV) DNA molecules: clustering patterns, novel variants and chimerism. Clin Virol 2002, 23:119-48.
• [40]Solivetti FM, Elia F, Latini A, Cota C, Cordiali-Fei P, Di Carlo A: AIDS-Kaposi Sarcoma and Classic Kaposi Sarcoma: are different ultrasound patterns related to different variants? J Exp Clin Cancer Res 2011, 30:40-5. BioMed Central Full Text
• [41]Strimmer K, von Haeseler A: Likelihood-mapping: A simple method to visualize phylogenetic content of a sequence alignment. Proc Natl Acad Sci U S A 1997, 94:6815-9.
• [42]Zehender G, Sorrentino C, Lai A, Ebranati E, Gabanelli E, Lo Presti A, et al.: Reconstruction of the evolutionary dynamics of hepatitis C virus subtypes in Montenegro and the Balkan region. Infect Genet Evol 2013, 17:223-30.
• [43]Ciccozzi M, Zehender G, Polat C, Lai A, Kayman T, Sorrentino C, et al.: Phylogenetic analysis of HCV-4d in Turkey: the curious case of Kayseri Province. J Med Virol 2014, 86:454-60.
• [44]de Oliveira T, Deforche K, Cassol S, Salminen M, Paraskevis D, Seebregts C, et al.: An automated genotyping system for analysis of HIV-1 and other microbial sequences. Bioinformatics 2005, 21:3797-800.
• [45]Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O: New Algorithms and Methods to Estimate Maximum-Likelihood Phylogenies: Assessing the Performance of PhyML 3.0. Syst Biol 2010, 59:307-21.
• [46]Posada D, Buckley TR: Model selection and model averaging in phylogenetics: advantages of akaike information criterion and bayesian approaches over likelihood ratio tests. Syst Biol 2004, 53:793-808.
• [47]Zehender G, Ebranati E, Bernini F, Lo Presti A, Rezza G, Delogu M, et al.: Phylogeography and epidemiological history of West Nile virus genotype 1a in Europe and the Mediterranean basin. Infect Genet Evol 2011, 11:646-53.
• [48]Drummond AJ, Rambaut A, Shapiro B, Pybus OG: Bayesian coalescent inference of past population dynamics from molecular sequences. Mol Biol Evol 2005, 22:1185-92.
• [49]Drummond AJ, Rambaut A: BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol 2007, 7:214. BioMed Central Full Text
• [50]Kass RE, Raftery AE: Bayes Factors. J Am Stat Assoc 1995, 90:773-95.
• [51]Yang Z: PAML: A program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 1997, 13:555-6.
• [52]Yang Z, Nielsen R, Goldman N, Pedersen AM: Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 2000, 155:431-49.
• [53]Nielsen R, Yang Z: Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 1998, 148:929-36.
• [54]Yang Z, Wong WS, Nielsen R: Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 2005, 22:1107-18.
• [55]Anisimova M, Bielawsky JP, Yang Z: Accuracy and power of likelihood ratio test in detecting adptive evolution. Mol Biol Evol 2001, 18:1585-92.
• [56]Anisimova M, Bielawsky JP, Yang Z: Accuracy and power of Bayes prediction of amino acid sites under positive selection. Mol Biol Evol 2002, 19:950-8.
• [57]Pond SK, Muse SV: Site-to-site variation of synonymous substitution rates. Mol Biol Evol 2005, 22:2375-85.
• [58]Kosakovsky Pond SL, Frost SDW: Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 2005, 22:1208-22.
• [59]Calabrò ML, Sheldon J, Favero A, Simpson GR, Fiore JR, Gomes E, et al.: Seroprevalence of Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8 in several regions of Italy. J Hum Virol 1998, 1:207-13.
• [60]Whitby D, Luppi M, Barozzi P, Boshoff C, Weiss RA, Torelli G: Human herpesvirus 8 seroprevalence in blood donors and lymphoma patients from different regions of Italy. J Natl Cancer Inst 1998, 90:395-7.
• [61]Lee BS, Lee SH, Feng P, Chang H, Cho NH, Jung JU: Characterization of the Kaposi’s Sarcoma –associated herpesvirus K1 signalosome. J Virol 2005, 79:12173-84.
• [62]Lee BS, Alvarez X, Ishido S, Lackner AA, Jung JU: Inhibition of intracellular transport of B cell antigen receptor complexes by Kaposi’s sarcoma-associated herpesvirus K1. J Exp Med 2000, 192:11-21.
• [63]Lee H, Veazey R, Williams K, Li M, Guo J, Neipel F, et al.: Deregulation of cell growth by the K1 gene of Kaposi’s sarcoma-associated herpesvirus. Nat Med 1998, 4:435-40.
• [64]Prakash O, Swamy OR, Peng X, Tang ZY, Li L, Larson JE, et al.: Activation of Src kinase Lyn by the Kaposi sarcoma-associated herpesvirus K1 protein: implications for lymphomagenesis. Blood 2005, 105:3987-94.
• [65]Samaniego F, Pati S, Karp JE, Prakash O, Bose D: Human herpesvirus 8 K1-associated nuclear factor-kappa B-dependent promoter activity: role in Kaposi’s sarcoma inflammation? J Natl Cancer Inst Monogr 2001, 28:15-23.
• [66]Pileri A, Agostinelli C, Righi S, Fuligni F, Bacci F, Sabattini E, Patrizi A, Pileri SA, Piccaluga PP. Vascular Endothelial Growth Factor A (Vegfa) Expression In Mycosis Fungoides. Histopathology 2014, 26. doi:10.1111/his.12445