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Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The purpose is to determine the incidence of active and latent human herpesvirus-6 (HHV-6) infection in a large cohort of adult primary and recurrent CNS tumors. We screened a tissue microarray (TMA) containing more than 200 adult primary and recurrent CNS tumors with known clinical information for the presence of HHV-6 DNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC). One hundred six of 224 (47%) CNS tumors were positive for HHV-6 U57 Major Capsid Protein (MCP) gene by ISH compared to 0/25 non tumor control brain (P = 0.001). Fourteen of 30 (47%) tumors were HHV-6 MCP positive by nested PCR compared to 0/25 non-tumor brain controls (P = 0.001), revealing HHV-6 Variant A in 6 of 14 samples. HHV-6A/B early (p41) and late (gp116/64/54) antigens were detected by IHC in 66 of 277 (24%) (P = 0.003) and 84 of 282 (35%) (P = 0.002) tumors, respectively, suggesting active infection. HHV-6 p41 (P = 0.645) and gp116/64/54 (P = 0.198) antigen detection was independent of recurrent disease. Glial tumors were 3 times more positive by IHC compared to non glial tumors for both HHV-6 gp116/64/54 (P = 0.0002) and HHV-6 p41 (P = 0.004). Kaplan Meier survival analysis showed no effect of HHV-6 gp116/64/54 (P = 0.852) or HHV-6 p41 (P = 0.817) antigen detection on survival. HHV-6 early and late antigens are detected in adult primary and recurrent CNS tumors more frequently in glial tumors. We hypothesize that the glial-tropic features of HHV-6 may play an important modifying role in tumor biology that warrants further investigation.

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References

  1. Caserta MT (2004) Human herpesvirus 6 infection of the central nervous system. Curr Infect Dis Rep 6:316–321. doi:10.1007/s11908-004-0054-x

    Article  PubMed  Google Scholar 

  2. De Bolle L, Naesens L, De Clercq E (2005) Update on human herpesvirus 6 biology, clinical features, and therapy. Clin Microbiol Rev 18:217–245. doi:10.1128/CMR.18.1.217-245.2005

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dockrell DH (2003) Human herpesvirus 6: molecular biology and clinical features. J Med Microbiol 52:5–18. doi:10.1099/jmm.0.05074-0

    Article  CAS  PubMed  Google Scholar 

  4. Stoeckle MY (2000) The spectrum of human herpesvirus 6 infection: from roseola infantum to adult disease. Annu Rev Med 51:423–430. doi:10.1146/annurev.med.51.1.423

    Article  CAS  PubMed  Google Scholar 

  5. Donati D, Akhyani N, Fogdell-Hahn A et al (2003) Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 61:1405–1411

    Article  CAS  PubMed Central  Google Scholar 

  6. Theodore WH, Epstein L, Gaillard WD, Shinnar S, Wainwright MS, Jacobson S (2008) Human herpes virus 6B: a possible role in epilepsy? Epilepsia 49:1828–1837

    Article  PubMed  PubMed Central  Google Scholar 

  7. Fotheringham J, Donati D, Akhyani N et al (2007) Association of human herpesvirus-6B with mesial temporal lobe epilepsy. PLoS Med 4:e180. doi:10.1371/journal.pmed.0040180

    Article  PubMed  PubMed Central  Google Scholar 

  8. Crawford JR, Kadom N, Santi MR, Mariani B, Lavenstein BL (2007) Human herpesvirus 6 rhombencephalitis in immunocompetent children. J Child Neurol 22:1260–1268. doi:10.1177/0883073807307086

    Article  PubMed  Google Scholar 

  9. Gewurz BE, Marty FM, Baden LR, Katz JT (2008) Human herpesvirus 6 encephalitis. Curr Infect Dis Rep 10:292–299. doi:10.1007/s11908-008-0048-1

    Article  PubMed  Google Scholar 

  10. Albright AV, Lavi E, Black JB, Goldberg S, O’Connor MJ, Gonzalez-Scarano F (1998) The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia. J Neurovirol 4:486–494

    Article  CAS  PubMed  Google Scholar 

  11. Kong H, Baerbig Q, Duncan L, Shepel N, Mayne M (2003) Human herpesvirus type 6 indirectly enhances oligodendrocyte cell death. J Neurovirol 9:539–550. doi:10.1080/713831641

    Article  CAS  PubMed  Google Scholar 

  12. Dietrich J, Blumberg BM, Roshal M et al (2004) Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties. J Neurosci 24:4875–4883. doi:10.1523/JNEUROSCI.5584-03.2004

    Article  CAS  PubMed  Google Scholar 

  13. Arena A, Liberto MC, Iannello D, Capozza AB, Foca A (1999) Altered cytokine production after human herpes virus type 6 infection. New Microbiol 22:293–300

    CAS  PubMed  Google Scholar 

  14. De Bolle L, Van Loon J, De Clercq E, Naesens L (2005) Quantitative analysis of human herpesvirus 6 cell tropism. J Med Virol 75:76–85. doi:10.1002/jmv.20240

    Article  PubMed  Google Scholar 

  15. Donati D, Martinelli E, Cassiani-Ingoni R et al (2005) Variant-specific tropism of human herpesvirus 6 in human astrocytes. J Virol 79:9439–9448. doi:10.1128/JVI.79.15.9439-9448.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chan PK, Ng HK, Cheng AF (1999) Detection of human herpesviruses 6 and 7 genomic sequences in brain tumours. J Clin Pathol 52:620–623. doi:10.1136/jcp.52.8.620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Luppi M, Barozzi P, Maiorana A et al (1995) Human herpesvirus-6: a survey of presence and distribution of genomic sequences in normal brain and neuroglial tumors. J Med Virol 47:105–111. doi:10.1002/jmv.1890470119

    Article  CAS  PubMed  Google Scholar 

  18. Cuomo L, Trivedi P, Cardillo MR et al (2001) Human herpesvirus 6 infection in neoplastic and normal brain tissue. J Med Virol 63:45–51. doi:10.1002/1096-9071(200101)63:1<45::AID-JMV1006>3.0.CO;2-K

    Article  CAS  PubMed  Google Scholar 

  19. Sallinen SL, Sallinen PK, Haapasalo HK et al (2000) Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res 60:6617–6622

    CAS  PubMed  Google Scholar 

  20. Fotheringham J, Akhyani N, Vortmeyer A et al (2007) Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid. J Infect Dis 195:450–454. doi:10.1086/510757

    Article  CAS  PubMed  Google Scholar 

  21. Yao K, Gagnon S, Akhyani N et al (2008) Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS ONE 3:e2028. doi:10.1371/journal.pone.0002028

    Article  PubMed  PubMed Central  Google Scholar 

  22. Akhyani N, Berti R, Brennan MB (2000) Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis. J Infect Dis 182:1321–1325. doi:10.1086/315893

    Article  CAS  PubMed  Google Scholar 

  23. Yao K, Mandel M, Akyani N et al (2006) Differential HHV-6A gene expression in T cells and primary human astrocytes based on multi-virus array analysis. Glia 53:789–798. doi:10.1002/glia.20333

    Article  PubMed  Google Scholar 

  24. Neves AM, Thompson G, Carvalheira J et al (2008) Detection and quantitative analysis of human herpesvirus in pilocytic astrocytoma. Brain Res 221:108–114. doi:10.1016/j.brainres.2008.05.009

    Article  Google Scholar 

  25. Tuke PW, Hawke S, Griffiths PD, Clark DA (2004) Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains. Mult Scler 10:355–359. doi:10.1191/1352458504ms1057oa

    Article  CAS  PubMed  Google Scholar 

  26. Gordon L, McQuaid S, Cosby SL (1996) Detection of herpes simplex virus types 1 and 2 and human herpesvirus 6 DNA in human brain tissue by polymerase chain reaction. Clin Diagn Virol 6:33–40. doi:10.1016/0928-0197(95)00203-0

    Article  CAS  PubMed  Google Scholar 

  27. Cermelli C, Berti R, Soldan SS et al (2003) High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection. J Infect Dis 187:1377–1387. doi:10.1086/368166

    Article  CAS  PubMed  Google Scholar 

  28. Friedman JE, Lyons MJ, Cu G et al (1999) The association of the human herpesvirus-6 and MS. Mult Scler 5:355–362

    Article  CAS  PubMed  Google Scholar 

  29. Liedtke W, Trübner K, Schwechheimer K (1995) On the role of human herpesvirus 6 in viral latency in nervous tissue and in cerebral lymphoma. J Neurol Sci 134:184–188. doi:10.1016/0022-510X(95)00248-6

    Article  CAS  PubMed  Google Scholar 

  30. Merelli E, Bedin R, Sola P et al (1997) Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children. J Neurol 244:450–454. doi:10.1007/s004150050121

    Article  CAS  PubMed  Google Scholar 

  31. Lin WR, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF (2002) Herpesviruses in brain and Alzheimer’s disease. J Pathol 197:395–402. doi:10.1002/path.1127

    Article  CAS  PubMed  Google Scholar 

  32. Flamand L, Gravel A, Boutolleau D et al (2008) Multicenter comparison of PCR assays for detection of human herpesvirus 6 DNA in serum. J Clin Microbiol 46:2700–2706. doi:10.1128/JCM.00370-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tanaka-Taya K, Sashihara J, Kurahashi H et al (2004) Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA. J Med Virol 73:465–473. doi:10.1002/jmv.20113

    Article  PubMed  Google Scholar 

  34. Daibata M, Taguchi T, Nemoto Y, Taguchi H, Miyoshi I (1999) Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood 94:1545–1549

    CAS  PubMed  Google Scholar 

  35. Kamble RT, Clark DA, Leong HN, Heslop HE, Brenner MK, Carrum G (2007) Transmission of integrated human herpesvirus-6 in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 40:563–566. doi:10.1038/sj.bmt.1705780

    Article  CAS  PubMed  Google Scholar 

  36. Leong HN, Tuke PW, Tedder RS et al (2007) The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. J Med Virol 79:45–51. doi:10.1002/jmv.20760

    Article  CAS  PubMed  Google Scholar 

  37. Clark DA, Nacheva EP, Leong HN et al (2006) Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. J Infect Dis 193:912–916. doi:10.1086/500838

    Article  PubMed  Google Scholar 

  38. Hall CB, Caserta MT, Schnabel K et al (2008) Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics 122:513–520. doi:10.1542/peds.2007-2838

    Article  PubMed  Google Scholar 

  39. Doniger J, Muralidhar S, Rosenthal LJ (1999) Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate. Clin Microbiol Rev 12:367–382

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kashanchi F, Araujo J, Doniger J et al (1997) Human herpesvirus 6 (HHV-6) ORF-1 transactivating gene exhibits malignant transforming activity and its protein binds to p53. Oncogene 14:359–367. doi:10.1038/sj.onc.1200840

    Article  CAS  PubMed  Google Scholar 

  41. Prins RM, Cloughesy TF, Liau LM (2008) Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 359:539–541. doi:10.1056/NEJMc0804818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mitchell DA, Archer GE, Bigner D et al (2008) Efficacy and immunologic effects of RNA-pulsed dendritic cell vaccines targeting human cytomegalovirus antigens in patients with glioblastoma [abstract]. In: Proceedings of the 99th Annual Meeting of the American Association for Cancer Research; Apr 12–16; San Diego, CA. Philadelphia (PA): AACR; 2008. Abstract LB 73

  43. Mitchell DA, Xie W, Schmittling R et al (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10:10–18. doi:10.1215/15228517-2007-035

    Article  PubMed  PubMed Central  Google Scholar 

  44. Poltermann S, Schlehofer B, Steindorf K, Schnitzler P, Geletneky K, Schlehofer JR (2006) Lack of association of herpesviruses with brain tumors. J Neurovirol 12:90–99. doi:10.1080/13550280600654573

    Article  CAS  PubMed  Google Scholar 

  45. Lau SK, Chen YY, Chen WG et al (2005) Lack of association of cytomegalovirus with human brain tumors. Mod Pathol 18:838–843. doi:10.1038/modpathol.3800352

    Article  CAS  PubMed  Google Scholar 

  46. Scheurer M, Bondy M, Aldape K, Albrecht T, El-Zein R (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116:79–86. doi:10.1007/s00401-008-0359-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cobbs CS, Harkins L, Samanta M et al (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62:3347–3350

    CAS  PubMed  Google Scholar 

  48. Vrsalovic MM, Korac P, Dominis M, Ostojic S, Mannhalter C, Kusec R (2004) T- and B-cell clonality and frequency of human herpes viruses-6, -8 and Epstein Barr virus in angioimmunoblastic T-cell lymphoma. Hematol Oncol 22:169–177. doi:10.1002/hon.740

    Article  PubMed  Google Scholar 

  49. Seror E, Coquerel B, Gautheret-Dejean A et al (2008) Quantitation of Human herpes virus 6 genome in children with acute lymphoblastic leukemia. J Med Virol 80:689–693. doi:10.1002/jmv.21118

    Article  CAS  PubMed  Google Scholar 

  50. Yamanishi K, Okuno T, Shiraki K et al (1998) Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1:1065–1067

    Google Scholar 

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Acknowlegements

The authors would like to thank Dr. Juha Kononen for gifting the adult tissue microarray and Dr. Elisabeth Rushing (Armed Forces Institute of Pathology, Washington DC) for providing the adult non tumor control tissue. We thank Dr. Steven Jacobson (National Institute of Neurological Disorders and Stroke) for providing positive control HHV-6 encephalitis material and infected cell lysate. This work was supported by the National Institutes of Health Neurological Sciences Academic Development Award (NSADA) K12NS052159-01A.

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Authors and Affiliations

  1. Department of Neurology, The George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA

    John R. Crawford

  2. Department of Pathology, The George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA

    Maria Rita Santi

  3. Department of Hematology-Oncology, The George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA

    Tobey J. MacDonald

  4. The Brain Tumor Institute, Children’s National Medical Center, The George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA

    John R. Crawford, Maria Rita Santi & Tobey J. MacDonald

  5. Molecular Genetics Section, The National Cancer Institute, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Robbie Cornelison

  6. Department of Pediatrics, Genetics Outpatient Clinics, Tampere University Hospital, P.O. Box 2000, Tampere, 33521, Finland

    Satu-Leena Sallinen

  7. Department of Pathology, Tampere University Hospital, P.O. Box 2000, Tampere, 33521, Finland

    Hannu Haapasalo

  8. Department of Neurology, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093, USA

    John R. Crawford

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  1. John R. Crawford
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Correspondence to John R. Crawford.

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Crawford, J.R., Santi, M.R., Cornelison, R. et al. Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors. J Neurooncol 95, 49–60 (2009). https://doi.org/10.1007/s11060-009-9908-2

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