Skip to main content
SpringerLink
Log in
Book cover

Maternal Fetal Transmission of Human Viruses and their Influence on Tumorigenesis pp 171–194Cite as

The Mechanism and Significance of Integration and Vertical Transmission of Human Herpesvirus 6 Genome

  • Chapter
  • First Online:

  • 655 Accesses

Abstract

The integration of HHV-6 into telomeres is a newly identified form of Human Herpesvirus latency. The integration of iHHV-6A and iHHV-6B into the same chromosome telomeres of family members lends itself to vertical transmission through the germ-line. Studies have shown that iHHV-6A and iHHV-6B preferentially integrated in chromosomes’ telomeres 9q34.4, 17p13.3, 18q23, 19q13.4, and 22q13.3.

Congenital or connatal HHV-6 infection occurs in up to 1% of infants and may be due to either transplacental infection or vertical transmission of the integrated virus. The humoral response to a primary HHV-6 infection differs from that to iHHV-6. A primary response leads to the production of anti-HHV-6 IgM and IgG antibodies, while only IgG antibodies have been detected in the serum of iHHV-6 patients. Evidence for immune tolerance and an altered immune response to HHV-6 have been detected, too. The presence of anti-IE-1 antibodies may indicate viral reactivation in iHHV-6 carriers.

In normal healthy blood donors it was found that 0.8–1.0% had high viral loads most likely attributed to iHHV-6 integration in the germ-line. The prevalence of integrated iHHV-6 in hospitalized patients was higher, 2.9–3.3%.

Will clinicians also have to consider screening for iHHV-6 during blood donations? It is yet unknown whether the integrated latent virus of the donor is capable of reactivation and subsequently infecting cells of the recipient resulting in possible pathological consequences. Future studies are required to determine the overall impact of the integrated virus whether it may have harmful effects on hospitalized patients and understand disease progression associated with iHHV-6.

The full length genome of EBV infrequently integrates into random chromosome sites during latency. The gammaherpesvirus Marek’s Disease Virus (MDV) frequently integrates into the telomere of chickens through telomeric repeats. Of the six shelterin proteins, TRF2 was shown to bind to the three nonamer EBV encoded TTAGGGTTA repeat within the origin of latent DNA replication (oriP) in cooperation with viral latency gene EBNA-1. It is hypothesized by the authors that the binding of telomere repeats encoded in the DR of HHV-6 by TRF2/TRF1 plays a role in telomere mediated integration by facilitating the localization of the viral genome to the telomere of chromosomes.

It is suggested, that ORF U94 may function as a latency gene and possibly facilitate HHV-6A/HHV-6B specific integration into telomeres similar to its AAV-2 encoded rep68/78 counterpart. The integration of HHV-6 into chromosomes is not a dead end pathway; the virus is shown to reactivate from its latent integrated state and leads to infection of naïve cells resulting in cell death. It is proposed that integration of HHV-6 into the telomere of chromosomes occurs through homologous recombination. However, it remains unknown whether the viral latency gene ORF U94 and telomere binding proteins TRF1 and TRF2 do in fact play a role during the process of integration. Furthermore, the physiological effect and impact on the stability of iHHV-6 has on the telomere remains unknown.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Ablashi DV, Devin CL, Yoshikawa T, Lautenschlager I, Luppi M, Kuhl U, Komaroff AL (2010) Review part 3: human herpesvirus-6 in multiple non-neurological diseases. J Med Virol 82:1903–1910. doi:10.1002/jmv.21860

    PubMed  Google Scholar 

  • Achour A, Malet I, Deback C, Bonnafous P, Boutolleau D, Gautheret-Dejean A, Agut H (2009) Length variability of telomeric repeat sequences of human herpesvirus 6 DNA. J Virol Methods 159:127–130. doi:10.1016/j.jviromet.2009.03.002

    PubMed  CAS  Google Scholar 

  • Ahlqvist J, Fotheringham J, Akhyani N, Yao K, Fogdell-Hahn A, Jacobson S (2005) Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes. J Neurovirol 11:384–394. doi:10.1080/13550280591002379

    PubMed  CAS  Google Scholar 

  • Anzai T, Takahashi H, Fujiwara H (2001) Sequence-specific recognition and cleavage of telomeric repeat (TTAGG)(n) by endonuclease of non-long terminal repeat retrotransposon TRAS1. Mol Cell Biol 21:100–108. doi:10.1128/MCB.21.1.100-108.2001

    PubMed  CAS  Google Scholar 

  • Araujo JC, Doniger J, Kashanchi F, Hermonat PL, Thompson J, Rosenthal LJ (1995) Human herpesvirus 6A ts suppresses both transformation by H-ras and transcription by the H-ras and human immunodeficiency virus type 1 promoters. J Virol 69:4933–4940

    PubMed  CAS  Google Scholar 

  • Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, Lunde TC, Tolare J, De Meirleir K, Montoyag JG, Komaroff AL, Ambrosc PF, Medveczky PG (2010) The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc Natl Acad Sci USA 107:5563–5568. doi:10.1073/pnas.0913586107

    PubMed  CAS  Google Scholar 

  • Asano Y, Yoshikawa T, Suga S, Kobayashi I, Nakashima T, Yazaki T, Kajita Y, Ozaki T (1994) Clinical features of infants with primary human herpesvirus 6 infection (exanthem subitum, roseola infantum). Pediatrics 93:104–108

    PubMed  CAS  Google Scholar 

  • Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318:798–801. doi:10.1126/science.1147182

    PubMed  CAS  Google Scholar 

  • Ballestas ME, Chatis PA, Kaye KM (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284:641–644. doi:10.1126/science.284.5414.641

    PubMed  CAS  Google Scholar 

  • Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Joukov V, Walter JC, Luger K, Kaye KM (2006) The nucleosomal surface as a docking station for Kaposi’s sarcoma herpesvirus LANA. Science 311:856–861. doi:10.1126/science.1120541

    PubMed  CAS  Google Scholar 

  • Borenstein R, Zeigerman H, Frenkel N (2010) The DR1 and DR6 first exons of human herpesvirus 6A are not required for virus replication in culture and are deleted in virus stocks that replicate well in T-cell lines. J Virol 84:2648–2656. doi:10.1128/JVI.01951-09

    PubMed  CAS  Google Scholar 

  • Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR (1997) Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 3:1271–1274. doi:10.1038/nm1197-1271

    PubMed  CAS  Google Scholar 

  • Cameron B, Flamand L, Juwana H, Middeldorp J, Naing Z, Rawlinson W, Ablashi D, Lloyd A (2010) Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome. J Med Virol 82:1684–1688. doi:10.1002/jmv.21873

    PubMed  CAS  Google Scholar 

  • Campadelli-Fiume G, Guerrini S, Liu X, Foa-Tomasi L (1993) Monoclonal antibodies to glycoprotein B differentiate human herpesvirus 6 into two clusters, variants A and B. J Gen Virol 74(Pt 10):2257–2262. doi:10.1099/0022-1317-74-10-2257

    PubMed  CAS  Google Scholar 

  • Caselli E, Boni M, Bracci A, Rotola A, Cermelli C, Castellazzi M, Di Luca D, Cassai E (2002) Detection of antibodies directed against human herpesvirus 6 U94/REP in sera of patients affected by multiple sclerosis. J Clin Microbiol 40:4131–4137. doi:10.1128/JCM.40.11.4131-4137.2002

    PubMed  CAS  Google Scholar 

  • Caselli E, Bracci A, Galvan M, Boni M, Rotola A, Bergamini C, Cermellic C, Dal Monte P, Gompelse UA, Cassaia E, Di Luca D (2006) Human herpesvirus 6 (HHV-6) U94/REP protein inhibits betaherpesvirus replication. Virology 346:402–414. doi:10.1016/j.virol.2005.11.018

    PubMed  CAS  Google Scholar 

  • Cermelli C, Berti R, Soldan SS, Mayne M, D’Ambrosia JM, Ludwin SK, Jacobson S (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

    PubMed  CAS  Google Scholar 

  • Clark DA, Nacheva EP, Leong HN, Brazma D, Li YT, Tsao EH, Buyck HCE, Atkinson CE, Lawson HM, Potter MN, Griffiths PD (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

    PubMed  Google Scholar 

  • Daibata M, Taguchi T, Taguchi H, Miyoshi I (1998) Integration of human herpesvirus 6 in a Burkitt’s lymphoma cell line. Br J Haematol 102:1307–1313. doi:10.1046/j.1365-2141.1998.00903.x

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • de Lange T (2004) T-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5:323–329. doi:10.1038/nrm1359

    PubMed  Google Scholar 

  • de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110. doi:10.1101/gad.1346005

    PubMed  Google Scholar 

  • Delecluse HJ, Hammerschmidt W (1993) Status of Marek’s disease virus in established lymphoma cell lines: herpesvirus integration is common. J Virol 67:82–92

    PubMed  CAS  Google Scholar 

  • Delecluse HJ, Schuller S, Hammerschmidt W (1993) Latent Marek’s disease virus can be activated from its chromosomally integrated state in herpesvirus-transformed lymphoma cells. EMBO J 12:3277–3286

    PubMed  CAS  Google Scholar 

  • Deng Z, Lezina L, Chen CJ, Shtivelband S, So W, Lieberman PM (2002) Telomeric proteins regulate episomal maintenance of Epstein-Barr virus origin of plasmid replication. Mol Cell 9:493–503. doi:10.1016/S1097-2765(02)00476-8

    PubMed  CAS  Google Scholar 

  • Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman PM (2009) TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell 35:403–413. doi:10.1016/j.molcel.2009.06.025

    PubMed  CAS  Google Scholar 

  • Dhepakson P, Mori Y, Jiang YB, Huang HL, Akkapaiboon P, Okuno T et al (2002) Human herpesvirus-6 rep/U94 gene product has single-stranded DNA-binding activity. J Gen Virol 83(Pt 4):847–854

    PubMed  CAS  Google Scholar 

  • Dockrell DH, Paya CV (2001) Human herpesvirus-6 and -7 in transplantation. Rev Med Virol 11:23–36

    PubMed  CAS  Google Scholar 

  • Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue N, Pellett PE (1999) Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol 73:8040–8052

    PubMed  CAS  Google Scholar 

  • Donati D, Akhyani N, Fogdell-Hahn A, Cermelli C, Cassiani-Ingoni R, Vortmeyer A, Heiss JD, Cogen P, Gaillard WD, Sato S, Theodore WH, Jacobson S (2003) Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 61:1405–1411

    PubMed  CAS  Google Scholar 

  • Fields BN, Knipe DM, Howley PM (eds) (2007) Fields virology, 5th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  • Fox JD, Ward P, Briggs M, Irving W, Stammers TG, Tedder RS (1990) Production of IgM antibody to HHV6 in reactivation and primary infection. Epidemiol Infect 104:289–296. doi:10.1017/S095026880005946X

    PubMed  CAS  Google Scholar 

  • Gao J, Luo X, Tang K, Li X, Li G (2006) Epstein-Barr virus integrates frequently into chromosome 4q, 2q, 1q and 7q of Burkitt’s lymphoma cell line (Raji). J Virol Methods 136:193–199

    PubMed  CAS  Google Scholar 

  • Gao J, Cai Q, Lu J, Jha HC, Robertson ES (2011) Upregulation of cellular Bcl-2 by the KSHV encoded RTA promotes virion production. PLoS One 6:e23892

    PubMed  CAS  Google Scholar 

  • Gardella T, Medveczky P, Sairenji T, Mulder C (1984) Detection of circular and linear herpesvirus DNA molecules in mammalian cells by gel electrophoresis. J Virol 50:248–254

    PubMed  CAS  Google Scholar 

  • Gompels UA, Nicholas J, Lawrence G, Jones M, Thomson BJ, Martin ME, Efstathiou S, Craxton M, Macaulay HA (1995) The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 209:29–51. doi:10.1006/viro.1995.1228

    PubMed  CAS  Google Scholar 

  • Hafler DA, Slavik JM, Anderson DE, O’Connor KC, De Jager P, Baecher-Allan C (2005) Multiple sclerosis. Immunol Rev 204:208–231. doi:10.1111/j.0105-2896.2005.00240.x

    PubMed  CAS  Google Scholar 

  • Hall CB, Caserta MT, Schnabel KC, Boettrich C, McDermott MP, Lofthus GK, Carnahan JA, Dewhurst S (2004) Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). J Pediatr 145:472–477. doi:10.1016/j.jpeds.2004.06.017

    PubMed  CAS  Google Scholar 

  • Hall CB, Caserta MT, Schnabel K, Shelley LM, Marino AS, Carnahan JA, Yoo C, Lofthus GK, McDermott MP (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

    PubMed  Google Scholar 

  • Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621. doi:10.1016/0014-4827(61)90192-6

    Google Scholar 

  • Henckaerts E, Dutheil N, Zeltner N, Kattman S, Kohlbrenner E, Ward P, Clément N, Rebollo P, Kennedy M, Keller GM, Linden RM (2009) Site-specific integration of adeno-associated virus involves partial duplication of the target locus. Proc Natl Acad Sci USA 106:7571–7576. doi:10.1073/pnas.0806821106

    PubMed  CAS  Google Scholar 

  • Henson JD, Neumann AA, Yeager TR, Reddel RR (2002) Alternative lengthening of telomeres in mammalian cells. Oncogene 21:598–610. doi:10.1038/sj.onc.1205058

    PubMed  CAS  Google Scholar 

  • Hickman AB, Ronning DR, Perez ZN, Kotin RM, Dyda F (2004) The nuclease domain of adeno-associated virus rep coordinates replication initiation using two distinct DNA recognition interfaces. Mol Cell 13:403–414. doi:10.1016/S1097-2765(04)00023-1

    PubMed  CAS  Google Scholar 

  • Hogquist KA, Baldwin TA, Jameson SC (2005) Central tolerance: learning self-control in the thymus. Nat Rev Immunol 5:772–782. doi:10.1038/nri1707

    PubMed  CAS  Google Scholar 

  • Hurley EA, Agger S, McNeil JA, Lawrence JB, Calendar A, Lenoir G, Thorley-Lawson DA (1991) When Epstein-Barr virus persistently infects B-cell lines, it frequently integrates. J Virol 65:1245–1254

    PubMed  CAS  Google Scholar 

  • Hüser D, Gogol-Döring A, Lutter T, Weger S, Winter K, Hammer EM, Cathomen T, Reinert K, Heilbronn R (2010) Integration preferences of wildtype AAV-2 for consensus rep-binding sites at numerous loci in the human genome. PLoS Pathog 6:e1000985

    PubMed  Google Scholar 

  • Im DS, Muzyczka N (1990) The AAV origin binding protein Rep68 is an ATP-dependent site-specific endonuclease with DNA helicase activity. Cell 61:447–457. doi:10.1016/0092-8674(90)90526-K

    PubMed  CAS  Google Scholar 

  • Isegawa Y, Mukai T, Nakano K, Kagawa M, Chen J, Mori Y, Sunagawa T, Kawanishi K, Sashihara J, Hata A, Zou P, Kosuge H, Yamanishi K (1999) Comparison of the complete DNA sequences of human herpesvirus 6 variants A and B. J Virol 73:8053–8063

    PubMed  CAS  Google Scholar 

  • Jacob RJ, Morse LS, Roizman B (1979) Anatomy of herpes simplex virus DNA. XII. Accumulation of head-to-tail concatemers in nuclei of infected cells and their role in the generation of the four isomeric arrangements of viral DNA. J Virol 29:448–457

    PubMed  CAS  Google Scholar 

  • James JA, Escalante CR, Yoon-Robarts M, Edwards TA, Linden RM, Aggarwal AK (2003) Crystal structure of the SF3 helicase from adeno-associated virus type 2. Structure 11:1025–1035. doi:10.1016/S0969-2126(03)00152-7

    PubMed  CAS  Google Scholar 

  • Jarrett RF, Gledhill S, Qureshi F, Crae SH, Madhok R, Brown I, Evans I, Krajewski A, O’Brien CJ, Cartwright RA et al (1988) Identification of human herpesvirus 6-specific DNA sequences in two patients with non-Hodgkin’s lymphoma. Leukemia 28:496–502

    Google Scholar 

  • Jeulin H, Salmon A, Gautheret-Dejean A, Agut H, Bordigoni P, Fortier B, Venard V (2009) Contribution of human herpesvirus 6 (HHV-6) viral load in whole blood and serum to investigate integrated HHV-6 transmission after haematopoietic stem cell transplantation. J Clin Virol 45:43–46. doi:10.1016/j.jcv.2009.02.006

    PubMed  CAS  Google Scholar 

  • Jones CM, Dunn HG, Thomas EE, Cone RW, Weber JM (1994) Acute encephalopathy and status epilepticus associated with human herpes virus 6 infection. Dev Med Child Neurol 36:646–650. doi:10.1111/j.1469-8749.1994.tb11903.x

    PubMed  CAS  Google Scholar 

  • 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 Transpl 40:563–566. doi:10.1038/sj.bmt.1705780

    CAS  Google Scholar 

  • Kawabata A, Oyaizu H, Maeki T, Tang H, Yamanishi K, Mori Y (2011) Analysis of a neutralizing antibody for human herpesvirus-6B reveals a role for glycoprotein Q1 in viral entry. J Virol 85:12962–12971. doi:10.1128/JVI.05622-11

    PubMed  CAS  Google Scholar 

  • Kondo K, Kondo T, Shimada K, Amo K, Miyagawa H, Yamanishi K (2002) Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection. J Med Virol 67:364–369. doi:10.1002/jmv.10082

    PubMed  CAS  Google Scholar 

  • Kondo K, Nozaki H, Shimada K, Yamanishi K (2003) Detection of a gene cluster that is dispensable for human herpesvirus 6 replication and latency. J Virol 77:10719–10724. doi:10.1128/JVI.77.19.10719-10724.2003

    PubMed  CAS  Google Scholar 

  • Lan K, Kuppers DA, Verma SC, Robertson ES (2004) Kaposi’s sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency. J Virol 78:6585–6594. doi:10.1128/JVI.78.12.6585-6594.2004

    PubMed  CAS  Google Scholar 

  • Leong HN, Tuke PW, Tedder RS, Khanom AB, Eglin RP, Atkinson CE, Ward KN, Griffith PD, Clark DA (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

    PubMed  CAS  Google Scholar 

  • Luppi M, Marasca R, Barozzi P, Ferrari S, Ceccherini-Nelli L, Batoni G, Merelli E, Torelli G (1993) Three cases of human herpesvirus-6 latent infection: integration of viral genome in peripheral blood mononuclear cell DNA. J Med Virol 40:44–52. doi:10.1002/jmv.1890400110

    PubMed  CAS  Google Scholar 

  • Lusso P, Ensoli B, Markham PD, Ablashi DV, Salahuddin SZ, Tschachler E, Wong-Stahl F, Gallo RC (1989) Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature 337:370–373. doi:10.1038/337370a0

    PubMed  CAS  Google Scholar 

  • Lusso P, Malnati M, De Maria A, Balotta C, DeRocco SE, Markham PD, Gallo RC (1991) Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3. J Immunol 147:685–691

    PubMed  CAS  Google Scholar 

  • Lusso P, Crowley RW, Malnati MS, Di Serio C, Ponzoni M, Biancotto A, Markham PD, Gallo RC (2007) Human herpesvirus 6A accelerates AIDS progression in macaques. Proc Natl Acad Sci USA 104:5067–5072. doi:10.1073/pnas.0700929104

    PubMed  CAS  Google Scholar 

  • Marechal V, Dehee A, Chikhi-Brachet R, Piolot T, Coppey-Moisan M, Nicolas JC (1999) Mapping EBNA-1 domains involved in binding to metaphase chromosomes. J Virol 73:4385–4392

    PubMed  CAS  Google Scholar 

  • Mori Y, Dhepakson P, Shimamoto T, Ueda K, Gomi Y, Tani H, Matsuura Y, Yamanishi K (2000) Expression of human herpesvirus 6B rep within infected cells and binding of its gene product to the TATA-binding protein in vitro and in vivo. J Virol 74:6096–6104. doi:10.1128/JVI.74.13.6096-6104.2000

    PubMed  CAS  Google Scholar 

  • Mori T, Tanaka-Taya K, Satoh H, Aisa Y, Yamazaki R, Kato J, Ikeda Y, Okamoto S (2009) Transmission of chromosomally integrated human herpesvirsus 6 (HHV-6) variant A from a parent to children leading to misdiagnosis of active HHV-6 infection. Transpl Infect Dis 11:503–506. doi:10.1111/j.1399-3062.2009.00430

    PubMed  CAS  Google Scholar 

  • Nacheva EP, Ward KN, Brazma D, Virgili A, Howard J, Leong HN, Clark DA (2008) Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal sites. J Med Virol 80:1952–1958. doi:10.1002/jmv.21299

    PubMed  Google Scholar 

  • Okazaki S, Ishikawa H, Fujiwara H (1995) Structural analysis of TRAS1, a novel family of telomeric repeat-associated retrotransposons in the silkworm, Bombyx mori. Mol Cell Biol 15:4545–4552

    PubMed  CAS  Google Scholar 

  • Okuno T, Takahashi K, Balachandra K, Shiraki K, Yamanishi K, Takahashi M, Baba K (1989) Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol 27:651–653

    PubMed  CAS  Google Scholar 

  • Osterrieder N, Kamil JP, Schumacher D, Tischer BK, Trapp S (2006) Marek’s disease virus: from miasma to model. Nat Rev Microbiol 4:283–294. doi:10.1038/nrmicro1382

    PubMed  CAS  Google Scholar 

  • Pfeiffer B, Berneman ZN, Neipel F, Chang CK, Tirwatnapong S, Chandran B (1993) Identification and mapping of the gene encoding the glycoprotein complex gp82-gp105 of human herpesvirus 6 and mapping of the neutralizing epitope recognized by monoclonal antibodies. J Virol 67:4611–4620

    PubMed  CAS  Google Scholar 

  • Poffenberger KL, Roizman B (1985) A noninverting genome of a viable herpes simplex virus 1: presence of head-to-tail linkages in packaged genomes and requirements for circularization after infection. J Virol 53:587–595

    PubMed  CAS  Google Scholar 

  • Raynaud CM, Sabatier L, Philipot O, Olaussen KA, Soria JC (2008) Telomere length, telomeric proteins and genomic instability during the multistep carcinogenic process. Crit Rev Oncol Hematol 66:99–117. doi:10.1016/j.critrevonc.2007.11.006

    PubMed  Google Scholar 

  • Reddel RR (2000) The role of senescence and immortalization in carcinogenesis. Carcinogenesis 21:477–484. doi:10.1093/carcin/21.3.477

    PubMed  CAS  Google Scholar 

  • Riethman H (2008) Human telomere structure and biology. Annu Rev Genomics Hum Genet 9:1–19. doi:10.1146/annurev.genom.8.021506.172017

    PubMed  CAS  Google Scholar 

  • Rotola A, Ravaioli T, Gonelli A, Dewhurst S, Cassai E, di Luca D (1998) U94 of human herpesvirus 6 is expressed in latently infected peripheral blood mononuclear cells and blocks viral gene expression in transformed lymphocytes in culture. Proc Natl Acad Sci USA 95:13911–13916. doi:10.1073/pnas.95.23.13911

    PubMed  CAS  Google Scholar 

  • Rotola A, Merlotti I, Caniatti L, Caselli E, Granieri E, Tola MR, Di Luca D, Cassai E (2004) Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease. Mult Scler 10:348–354. doi:10.1191/1352458504ms1045oa

    PubMed  CAS  Google Scholar 

  • Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, Halligan G, Biberfeld P, Wong-Staal F, Kramarsky B, Gallo RC (1986) Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234:596–601. doi:10.1126/science.2876520

    PubMed  CAS  Google Scholar 

  • Samulski RJ, Zhu X, Xiao X, Brook JD, Housman DE, Epstein N, Hunter LA (1991) Targeted integration of adeno-associated virus (AAV) into human chromosome 19. EMBO J 10:3941–3950

    PubMed  CAS  Google Scholar 

  • Sandel PC, Monroe JG (1999) Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. Immunity 10:289–299. doi:10.1016/S1074-7613(00)80029-1

    PubMed  CAS  Google Scholar 

  • Santoro F, Kennedy PE, Locatelli G, Malnati MS, Berger EA, Lusso P (1999) CD46 is a cellular receptor for human herpesvirus 6. Cell 99:817–827. doi:10.1016/S0092-8674(00)81678-5

    PubMed  CAS  Google Scholar 

  • Secchiero P, Nicholas J, Deng H, Xiaopeng T, van Loon N, Ruvolo VR, Berneman ZN, Reitz MS Jr, Dewhurst S (1955) Identification of human telomeric repeat motifs at the genome termini of human herpesvirus 7: structural analysis and heterogeneity. J Virol 69:8041–8045

    Google Scholar 

  • Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33:787–791. doi:10.1016/S0959-8049(97)00062-2

    PubMed  CAS  Google Scholar 

  • Soldan SS, Leist TP, Juhng KN, McFarland HF, Jacobson S (2000) Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients. Ann Neurol 47:306–313. doi:10.1002/1531-8249(200003)47:3<306::AID-ANA5>3.3.CO;2-1

    PubMed  CAS  Google Scholar 

  • Strenger V, Aberle SW, Wendelin G, Pfurtscheller K, Nacheva EP, Zobel G, Nagel B (2010) Chromosomal integration of the HHV-6 genome as a possible cause of HHV-6 detection in cardiac tissues. J Clin Pathol 63:1129–1130. doi:10.1136/jcp. 2010.079277

    PubMed  Google Scholar 

  • Takahashi K, Sonoda S, Higashi K, Kondo T, Takahashi H, Takahashi M, Yamanishi K (1989) Predominant CD4 T-lymphocyte tropism of human herpesvirus 6-related virus. J Virol 63:3161–3163

    PubMed  CAS  Google Scholar 

  • Takeda K, Okuno T, Isegawa Y, Yamanishi K (1996) Identification of a variant A-specific neutralizing epitope on glycoprotein B (gB) of human herpesvirus-6 (HHV-6). Virology 222:176–183. doi:10.1006/viro.1996.0408

    PubMed  CAS  Google Scholar 

  • Takeda K, Haque M, Sunagawa T, Okuno T, Isegawa Y, Yamanishi K (1997) Identification of a variant B-specific neutralizing epitope on glycoprotein H of human herpesvirus-6. J Gen Virol 78(Pt 9):2171–2178

    PubMed  CAS  Google Scholar 

  • Tanaka-Taya K, Sashihara J, Kurahashi H, Amo K, Miyagawa H, Kondo K (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

    PubMed  Google Scholar 

  • Thomson BJ, Efstathiou S, Honess RW (1991) Acquisition of the human adeno-associated virus type-2 rep gene by human herpesvirus type-6. Nature 351:78–80. doi:10.1038/351078a0

    PubMed  CAS  Google Scholar 

  • Thomson BJ, Weindler FW, Gray D, Schwaab V, Heilbronn R (1994) Human herpesvirus 6 (HHV-6) is a helper virus for adeno-associated virus type 2 (AAV-2) and the AAV-2 rep gene homologue in HHV-6 can mediate AAV-2 DNA replication and regulate gene expression. Virology 204:304–311. doi:10.1006/viro.1994.1535

    PubMed  CAS  Google Scholar 

  • Tomaska L, Nosek J, Kramara J, Griffith JD (2009) Telomeric circles: universal players in telomere maintenance? Nat Struct Mol Biol 16:1010–1015. doi:10.1038/nsmb.1660

    PubMed  CAS  Google Scholar 

  • Torelli G, Barozzi P, Marasca R, Cocconcelli P, Merelli E, Ceccherini-Nelli L, Ferrari S, Luppi M (1995) Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo. J Med Virol 46:178–188. doi:10.1002/jmv.1890460303

    PubMed  CAS  Google Scholar 

  • Troy SB, Blackburn BG, Yeom K, Caulfield AK, Bhangoo MS, Montoya JG (2008) Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir. Clin Infect Dis 47:e93–e96. doi:10.1086/593315

    PubMed  CAS  Google Scholar 

  • Verma SC, Choudhuri T, Kaul R, Robertson ES (2006a) Latency-associated nuclear antigen (LANA) of Kaposi’s sarcoma-associated herpesvirus interacts with origin recognition complexes at the LANA binding sequence within the terminal repeats. J Virol 80:2243–2256. doi:10.1128/JVI.80.5.2243-2256.2006

    PubMed  CAS  Google Scholar 

  • Verma SC, Lan K, Choudhuri T, Robertson ES (2006b) Kaposi’s sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen modulates K1 expression through its cis-acting elements within the terminal repeats. J Virol 80:3445–3458. doi:10.1128/JVI.80.7.3445-3458.2006

    PubMed  CAS  Google Scholar 

  • Ward KN, Thiruchelvam AD, Couto-Parada X (2005) Unexpected occasional persistence of high levels of HHV-6 DNA in sera: detection of variants A and B. J Med Virol 76:563–570. doi:10.1002/jmv.20399

    PubMed  CAS  Google Scholar 

  • Ward KN, Leong HN, Nacheva EP, Howard J, Atkinson CE, Davies NW, Grriffith PD, Clark DA (2006) Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles. J Clin Microbiol 44:1571–1574. doi:10.1128/JCM.44.4.1571-1574.2006

    PubMed  CAS  Google Scholar 

  • Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, Kurata T (1988) Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1:1065–1067. doi:10.1016/S0140-6736(88)91893-4

    PubMed  CAS  Google Scholar 

  • Yamashita N, Morishima T (2005) HHV-6 and seizures. Herpes 12:46–49

    PubMed  Google Scholar 

  • Yao K, Gagnon S, Akhyani N, Williams E, Fotheringham J, Frohman E, Stuve O, Monson N, Racke MK, Jacobson S (2008) Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS One 3:e2028. doi:10.1371/journal.pone.0002028

    PubMed  Google Scholar 

  • Yao K, Crawford JR, Komaroff AL, Ablashi DV, Jacobson S (2010) Review part 2: human herpesvirus-6 in central nervous system diseases. J Med Virol 82:1669–1678. doi:10.1002/jmv.21861

    PubMed  Google Scholar 

  • Zhou J, Snyder AR, Lieberman PM (2009) Epstein-Barr virus episome stability is coupled to a delay in replication timing. J Virol 83:2154–2162. doi:10.1128/JVI.02115-08

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA

    Jesse H. Arbuckle, Shara Pantry & Peter G. Medveczky

  2. Molecular Genetics Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, MD, USA

    Jesse H. Arbuckle

Authors
  1. Jesse H. Arbuckle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shara Pantry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter G. Medveczky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter G. Medveczky .

Editor information

Editors and Affiliations

  1. , Division of Virology, National Center for Epidemiology, Gyáli Street 2-6, Budapest, 1096, Hungary

    György Berencsi III

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Arbuckle, J.H., Pantry, S., Medveczky, P.G. (2012). The Mechanism and Significance of Integration and Vertical Transmission of Human Herpesvirus 6 Genome. In: Berencsi III, G. (eds) Maternal Fetal Transmission of Human Viruses and their Influence on Tumorigenesis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4216-1_5

Download citation

Publish with us

Policies and ethics

Search

Navigation