Latency, Integration, and Reactivation of Human Herpesvirus-6
<p>Genome organization of human herpesvirus-6 (HHV-6). Solid lines represent the unique length (U) regions of the genome, boxed regions represent repetitive elements of the genome, and the black boxes represent the perfect telomere repeats, while the gray boxes represent the imperfect telomere repeats. DR<sub>L</sub>: Direct repeat left; DR<sub>R</sub>: Direct repeat right; pac1, pac2: Packaging signals; R0–3: Repetitive elements.</p> "> Figure 2
<p>Model for integration and reactivation of HHV-6. The linear genome of HHV-6 integrates into the telomeres of the host chromosome, and during reactivation the integrated genome is liberated from the host chromosome, forming a circular intermediate. Rolling circle replication of the circular intermediate generates concatemers of the viral genome.</p> "> Figure 3
<p>Possible integration configurations of the HHV-6 genome. (<b>A</b>) The HHV-6 genome contains four telomere-like repeats flanking the direct repeats; (<b>B</b>) Integration of the HHV-6 genome by recombination with the host telomeres can potentially occur at either of the four telomere repeats and five possible integration configurations may be generated.</p> ">
Abstract
:1. The Discovery of HHV-6
2. Biological Differences between HHV-6A and HHV-6B
3. Epidemiology of HHV-6
4. HHV-6 Genome Structure
5. Integration of HHV-6 in Telomeres during Latency
6. Structure and Orientation of the Telomere-Integrated Viral Genome
7. Role of HHV-6 Telomeres and U94 in Integration
8. In Vitro Reactivation of Integrated HHV-6 from Infected Cells Harboring Latent HHV-6
9. Superinfection of iciHHV-6 Individuals with a Second Virus and Reactivation of iciHHV-6
10. Hypomethylation of Subtelomere Regions, HHV-6B Integration and Pathogenesis
11. Future of the Field of HHV-6
Conflicts of Interest
References
- Salahuddin, S.Z.; Ablashi, D.V.; Markham, P.D.; Josephs, S.F.; Sturzenegger, S.; Kaplan, M.; Halligan, G.; Biberfeld, P.; Wong-Staal, F.; Kramarsky, B.; et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986, 234, 596–601. [Google Scholar] [CrossRef] [PubMed]
- Lusso, P.; Malnati, M.; De Maria, A.; Balotta, C.; DeRocco, S.E.; Markham, P.D.; Gallo, R.C. Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3. J. Immunol. 1991, 147, 685–691. [Google Scholar] [PubMed]
- Lusso, P.; Markham, P.D.; Tschachler, E.; di Marzo Veronese, F.; Salahuddin, S.Z.; Ablashi, D.V.; Pahwa, S.; Krohn, K.; Gallo, R.C. In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6). J. Exp. Med. 1988, 167, 1659–1670. [Google Scholar] [CrossRef]
- Takahashi, K.; Sonoda, S.; Higashi, K.; Kondo, T.; Takahashi, H.; Takahashi, M.; Yamanishi, K. Predominant CD4 T-lymphocyte tropism of human herpesvirus 6-related virus. J. Virol. 1989, 63, 3161–3163. [Google Scholar] [PubMed]
- Yasukawa, M.; Yakushijin, Y.; Furukawa, M.; Fujita, S. Specificity analysis of human CD4+ T-cell clones directed against human herpesvirus 6 (HHV-6), HHV-7, and human cytomegalovirus. J. Virol. 1993, 67, 6259–6264. [Google Scholar] [PubMed]
- Schirmer, E.C.; Wyatt, L.S.; Yamanishi, K.; Rodriguez, W.J.; Frenkel, N. Differentiation between two distinct classes of viruses now classified as human herpesvirus 6. Proc. Natl. Acad. Sci. USA 1991, 88, 5922–5926. [Google Scholar] [CrossRef] [PubMed]
- Ablashi, D.V.; Balachandran, N.; Josephs, S.F.; Hung, C.L.; Krueger, G.R.; Kramarsky, B.; Salahuddin, S.Z.; Gallo, R.C. Genomic polymorphism, growth properties, and immunologic variations in human herpesvirus-6 isolates. Virology 1991, 184, 545–552. [Google Scholar] [CrossRef]
- Ablashi, D.; Agut, H.; Alvarez-Lafuente, R.; Clark, D.A.; Dewhurst, S.; DiLuca, D.; Flamand, L.; Frenkel, N.; Gallo, R.; Gompels, U.A.; et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch. Virol. 2014, 159, 863–870. [Google Scholar] [CrossRef] [PubMed]
- Liszewski, M.K.; Post, T.W.; Atkinson, J.P. Membrane cofactor protein (MCP or CD46): Newest member of the regulators of complement activation gene cluster. Annu. Rev. Immunol. 1991, 9, 431–455. [Google Scholar] [CrossRef] [PubMed]
- Tang, H.; Serada, S.; Kawabata, A.; Ota, M.; Hayashi, E.; Naka, T.; Yamanishi, K.; Mori, Y. CD134 is a cellular receptor specific for human herpesvirus-6B entry. Proc. Natl. Acad. Sci. USA 2013, 110, 9096–9099. [Google Scholar] [CrossRef] [PubMed]
- Tang, H.; Mori, Y. Determinants of human CD134 essential for entry of human herpesvirus 6B. J. Virol. 2015, 89, 10125–10129. [Google Scholar] [CrossRef] [PubMed]
- Jasirwan, C.; Furusawa, Y.; Tang, H.; Maeki, T.; Mori, Y. Human herpesvirus-6A gQ1 and gQ2 are critical for human CD46 usage. Microbiol. Immunol. 2014, 58, 22–30. [Google Scholar] [CrossRef] [PubMed]
- Hansen, A.S.; Bundgaard, B.B.; Biltoft, M.; Rossen, L.S.; Hollsberg, P. Divergent tropism of HHV-6AGS and HHV-6BPl1 in T cells expressing different CD46 isoform patterns. Virology 2017, 502, 160–170. [Google Scholar] [CrossRef] [PubMed]
- Achour, A.; Malet, I.; Le Gal, F.; Dehee, A.; Gautheret-Dejean, A.; Bonnafous, P.; Agut, H. Variability of gB and gH genes of human herpesvirus-6 among clinical specimens. J. Med. Virol. 2008, 80, 1211–1221. [Google Scholar] [CrossRef] [PubMed]
- Ward, K.N.; Gray, J.J.; Fotheringham, M.W.; Sheldon, M.J. IgG antibodies to human herpesvirus-6 in young children: Changes in avidity of antibody correlate with time after infection. J. Med. Virol. 1993, 39, 131–138. [Google Scholar] [CrossRef] [PubMed]
- Bates, M.; Monze, M.; Bima, H.; Kapambwe, M.; Clark, D.; Kasolo, F.C.; Gompels, U.A. Predominant human herpesvirus 6 variant a infant infections in an HIV-1 endemic region of sub-Saharan Africa. J. Med. Virol. 2009, 81, 779–789. [Google Scholar] [CrossRef] [PubMed]
- Tembo, J.; Kabwe, M.; Chilukutu, L.; Chilufya, M.; Mwaanza, N.; Chabala, C.; Zumla, A.; Bates, M. Prevalence and risk factors for betaherpesvirus DNAemia in children >3 weeks and <2 years of age admitted to a large referral hospital in sub-saharan africa. Clin. Infect. Dis. 2015, 60, 423–431. [Google Scholar]
- Wang, F.Z.; Dahl, H.; Ljungman, P.; Linde, A. Lymphoproliferative responses to human herpesvirus-6 variant a and variant b in healthy adults. J. Med. Virol. 1999, 57, 134–139. [Google Scholar] [CrossRef]
- Jayavasu, C.; Balachandra, K.; Wongchuree, S.; Kositanont, U.; Warachit, P. The latency rate of human herpesvirus 6 (HHV6) in positive and negative human immunodeficiency virus (HIV) infection of intravenous drug users (IVDU). Asian Pac. J. Allergy Immunol. 1997, 15, 29–33. [Google Scholar] [PubMed]
- Yamanishi, K.; Okuno, T.; Shiraki, K.; Takahashi, M.; Kondo, T.; Asano, Y.; Kurata, T. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988, 1, 1065–1067. [Google Scholar] [CrossRef]
- Tanaka, K.; Kondo, T.; Torigoe, S.; Okada, S.; Mukai, T.; Yamanishi, K. Human herpesvirus 7: Another causal agent for roseola (exanthem subitum). J Pediatr 1994, 125, 1–5. [Google Scholar] [CrossRef]
- Torigoe, S.; Kumamoto, T.; Koide, W.; Taya, K.; Yamanishi, K. Clinical manifestations associated with human herpesvirus 7 infection. Arch Dis Child 1995, 72, 518–519. [Google Scholar] [CrossRef] [PubMed]
- Ablashi, D.V.; Lapps, W.; Kaplan, M.; Whitman, J.E.; Richert, J.R.; Pearson, G.R. Human herpesvirus-6 (HHV-6) infection in multiple sclerosis: A preliminary report. Mult. Scler. 1998, 4, 490–496. [Google Scholar] [CrossRef] [PubMed]
- Ben-Fredj, N.; Ben-Selma, W.; Rotola, A.; Nefzi, F.; Benedetti, S.; Frih-Ayed, M.; Di Luca, D.; Aouni, M.; Caselli, E. Prevalence of human herpesvirus U94/Rep antibodies and DNA in tunisian multiple sclerosis patients. J. Neurovirol. 2013, 19, 42–47. [Google Scholar] [CrossRef] [PubMed]
- Soldan, S.S.; Berti, R.; Salem, N.; Secchiero, P.; Flamand, L.; Calabresi, P.A.; Brennan, M.B.; Maloni, H.W.; McFarland, H.F.; Lin, H.C.; et al. Association of human herpes virus 6 (HHV-6) with multiple sclerosis: Increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat. Med. 1997, 3, 1394–1397. [Google Scholar] [CrossRef] [PubMed]
- Ablashi, D.V.; Eastman, H.B.; Owen, C.B.; Roman, M.M.; Friedman, J.; Zabriskie, J.B.; Peterson, D.L.; Pearson, G.R.; Whitman, J.E. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J. Clin. Virol. 2000, 16, 179–191. [Google Scholar] [CrossRef]
- Komaroff, A.L. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J. Clin. Virol. 2006, 37 (Suppl. S1), S39–S46. [Google Scholar] [CrossRef]
- Montoya, J.G.; Neely, M.N.; Gupta, S.; Lunn, M.R.; Loomis, K.S.; Pritchett, J.C.; Polsky, B.; Medveczky, P.G. Antiviral therapy of two patients with chromosomally-integrated human herpesvirus-6A presenting with cognitive dysfunction. J. Clin. Virol. 2012, 55, 40–45. [Google Scholar] [CrossRef] [PubMed]
- Isegawa, Y.; Mukai, T.; Nakano, K.; Kagawa, M.; Chen, J.; Mori, Y.; Sunagawa, T.; Kawanishi, K.; Sashihara, J.; Hata, A.; et al. Comparison of the complete DNA sequences of human herpesvirus 6 variants A and B. J. Virol. 1999, 73, 8053–8063. [Google Scholar] [PubMed]
- Gompels, U.A.; Macaulay, H.A. Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication. J. Gen. Virol. 1995, 76 Pt 2, 451–458. [Google Scholar] [CrossRef] [PubMed]
- Dominguez, G.; Dambaugh, T.R.; Stamey, F.R.; Dewhurst, S.; Inoue, N.; Pellett, P.E. Human herpesvirus 6B genome sequence: Coding content and comparison with human herpesvirus 6A. J. Virol. 1999, 73, 8040–8052. [Google Scholar] [PubMed]
- Thomson, B.J.; Dewhurst, S.; Gray, D. Structure and heterogeneity of the a sequences of human herpesvirus 6 strain variants U1102 and Z29 and identification of human telomeric repeat sequences at the genomic termini. J. Virol. 1994, 68, 3007–3014. [Google Scholar] [PubMed]
- Gravel, A.; Hall, C.B.; Flamand, L. Sequence analysis of transplacentally acquired human herpesvirus 6 DNA is consistent with transmission of a chromosomally integrated reactivated virus. J. Infect. Dis. 2013, 207, 1585–1589. [Google Scholar] [CrossRef] [PubMed]
- Kondo, K.; Kondo, T.; Okuno, T.; Takahashi, M.; Yamanishi, K. Latent human herpesvirus 6 infection of human monocytes/macrophages. J. Gen. Virol. 1991, 72 Pt 6, 1401–1408. [Google Scholar] [CrossRef] [PubMed]
- Luppi, M.; Barozzi, P.; Morris, C.; Maiorana, A.; Garber, R.; Bonacorsi, G.; Donelli, A.; Marasca, R.; Tabilio, A.; Torelli, G. Human herpesvirus 6 latently infects early bone marrow progenitors in vivo. J. Virol. 1999, 73, 754–759. [Google Scholar] [PubMed]
- Arbuckle, J.H.; Medveczky, M.M.; Luka, J.; Hadley, S.H.; Luegmayr, A.; Ablashi, D.; Lund, T.C.; Tolar, J.; De Meirleir, K.; Montoya, J.G.; et al. The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc. Natl. Acad. Sci. USA 2010, 107, 5563–5568. [Google Scholar] [CrossRef] [PubMed]
- Arbuckle, J.H.; Pantry, S.N.; Medveczky, M.M.; Prichett, J.; Loomis, K.S.; Ablashi, D.; Medveczky, P.G. Mapping the telomere integrated genome of human herpesvirus 6A and 6B. Virology 2013, 442, 3–11. [Google Scholar] [CrossRef] [PubMed]
- Yoshikawa, T.; Asano, Y.; Akimoto, S.; Ozaki, T.; Iwasaki, T.; Kurata, T.; Goshima, F.; Nishiyama, Y. Latent infection of human herpesvirus 6 in astrocytoma cell line and alteration of cytokine synthesis. J. Med. Virol. 2002, 66, 497–505. [Google Scholar] [CrossRef] [PubMed]
- Ahlqvist, J.; Fotheringham, J.; Akhyani, N.; Yao, K.; Fogdell-Hahn, A.; Jacobson, S. Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes. J. Neurovirol. 2005, 11, 384–394. [Google Scholar] [CrossRef] [PubMed]
- Luppi, M.; Marasca, R.; Barozzi, P.; Ferrari, S.; Ceccherini-Nelli, L.; Batoni, G.; Merelli, E.; Torelli, G. Three cases of human herpesvirus-6 latent infection: Integration of viral genome in peripheral blood mononuclear cell DNA. J. Med. Virol. 1993, 40, 44–52. [Google Scholar] [CrossRef] [PubMed]
- Tanaka-Taya, K.; Sashihara, J.; Kurahashi, H.; Amo, K.; Miyagawa, H.; Kondo, K.; Okada, S.; Yamanishi, K. 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. 2004, 73, 465–473. [Google Scholar] [CrossRef] [PubMed]
- Hall, C.B.; Caserta, M.T.; Schnabel, K.; Shelley, L.M.; Marino, A.S.; Carnahan, J.A.; Yoo, C.; Lofthus, G.K.; McDermott, M.P. Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics 2008, 122, 513–520. [Google Scholar] [CrossRef] [PubMed]
- Daibata, M.; Taguchi, T.; Nemoto, Y.; Taguchi, H.; Miyoshi, I. Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood 1999, 94, 1545–1549. [Google Scholar] [PubMed]
- Leong, H.N.; Tuke, P.W.; Tedder, R.S.; Khanom, A.B.; Eglin, R.P.; Atkinson, C.E.; Ward, K.N.; Griffiths, P.D.; Clark, D.A. The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. J. Med. Virol. 2007, 79, 45–51. [Google Scholar] [CrossRef] [PubMed]
- Ljungman, P.; Wang, F.Z.; Clark, D.A.; Emery, V.C.; Remberger, M.; Ringden, O.; Linde, A. High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients. Br. J. Haematol. 2000, 111, 774–781. [Google Scholar] [PubMed]
- Clark, D.A.; Nacheva, E.P.; Leong, H.N.; Brazma, D.; Li, Y.T.; Tsao, E.H.; Buyck, H.C.; Atkinson, C.E.; Lawson, H.M.; Potter, M.N.; et al. Transmission of integrated human herpesvirus 6 through stem cell transplantation: Implications for laboratory diagnosis. J. Infect. Dis. 2006, 193, 912–916. [Google Scholar] [CrossRef] [PubMed]
- Ward, K.N.; Leong, H.N.; Nacheva, E.P.; Howard, J.; Atkinson, C.E.; Davies, N.W.; Griffiths, P.D.; Clark, D.A. Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles. J. Clin. Microbiol. 2006, 44, 1571–1574. [Google Scholar] [CrossRef] [PubMed]
- Caserta, M.T.; Hall, C.B.; Schnabel, K.; Lofthus, G.; Marino, A.; Shelley, L.; Yoo, C.; Carnahan, J.; Anderson, L.; Wang, H. Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). J. Clin. Virol. 2010, 48, 55–57. [Google Scholar] [CrossRef] [PubMed]
- Gulve, N.; Frank, C.; Klepsch, M.; Prusty, B.K. Chromosomal integration of HHV-6A during non-productive viral infection. Sci. Rep. 2017, 7, 512. [Google Scholar] [CrossRef] [PubMed]
- Ohye, T.; Inagaki, H.; Ihira, M.; Higashimoto, Y.; Kato, K.; Oikawa, J.; Yagasaki, H.; Niizuma, T.; Takahashi, Y.; Kojima, S.; et al. Dual roles for the telomeric repeats in chromosomally integrated human herpesvirus-6. Sci. Rep. 2014, 4, 4559. [Google Scholar] [CrossRef] [PubMed]
- Wallaschek, N.; Sanyal, A.; Pirzer, F.; Gravel, A.; Mori, Y.; Flamand, L.; Kaufer, B.B. The telomeric repeats of human herpesvirus 6A (HHV-6A) are required for efficient virus integration. PLoS Pathog. 2016, 12, e1005666. [Google Scholar] [CrossRef] [PubMed]
- Gravel, A.; Dubuc, I.; Wallaschek, N.; Gilbert-Girard, S.; Collin, V.; Hall-Sedlak, R.; Jerome, K.R.; Mori, Y.; Carbonneau, J.; Boivin, G.; et al. Cell culture systems to study human herpesvirus 6A/B chromosomal integration. J. Virol. 2017. [Google Scholar] [CrossRef] [PubMed]
- Trempe, F.; Gravel, A.; Dubuc, I.; Wallaschek, N.; Collin, V.; Gilbert-Girard, S.; Morissette, G.; Kaufer, B.B.; Flamand, L. Characterization of human herpesvirus 6A/B U94 as atpase, helicase, exonuclease and DNA-binding proteins. Nucleic Acids Res. 2015, 43, 6084–6098. [Google Scholar] [CrossRef] [PubMed]
- Thomson, B.J.; Weindler, F.W.; Gray, D.; Schwaab, V.; Heilbronn, R. 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 1994, 204, 304–311. [Google Scholar] [CrossRef] [PubMed]
- Thomson, B.J.; Efstathiou, S.; Honess, R.W. Acquisition of the human adeno-associated virus type-2 rep gene by human herpesvirus type-6. Nature 1991, 351, 78–80. [Google Scholar] [CrossRef] [PubMed]
- Wallaschek, N.; Gravel, A.; Flamand, L.; Kaufer, B.B. The putative U94 integrase is dispensable for human herpesvirus 6 (HHV-6) chromosomal integration. J. Gen. Virol. 2016, 97, 1899–1903. [Google Scholar] [CrossRef] [PubMed]
- Gardella, T.; Medveczky, P.; Sairenji, T.; Mulder, C. Detection of circular and linear herpesvirus DNA molecules in mammalian cells by gel electrophoresis. J. Virol. 1984, 50, 248–254. [Google Scholar] [PubMed]
- Pantry, S.N.; Medveczky, M.M.; Arbuckle, J.H.; Luka, J.; Montoya, J.G.; Hu, J.; Renne, R.; Peterson, D.; Pritchett, J.C.; Ablashi, D.V.; et al. Persistent human herpesvirus-6 infection in patients with an inherited form of the virus. J. Med. Virol. 2013, 85, 1940–1946. [Google Scholar] [CrossRef] [PubMed]
- Tweedy, J.; Spyrou, M.A.; Pearson, M.; Lassner, D.; Kuhl, U.; Gompels, U.A. Complete genome sequence of germline chromosomally integrated human herpesvirus 6A and analyses integration sites define a new human endogenous virus with potential to reactivate as an emerging infection. Viruses 2016, 8, 19. [Google Scholar] [CrossRef] [PubMed]
- Engdahl, E.; Dunn, N.; Niehusmann, P.; Wideman, S.; Wipfler, P.; Becker, A.J.; Ekstrom, T.J.; Almgren, M.; Fogdell-Hahn, A. Human herpesvirus 6B induces hypomethylation on chromosome 17p13.3, correlating with increased gene expression and virus integration. J. Virol. 2017, 91. [Google Scholar] [CrossRef] [PubMed]
- Daibata, M.; Taguchi, T.; Kubonishi, I.; Taguchi, H.; Miyoshi, I. Lymphoblastoid cell lines with integrated human herpesvirus type 6. J. Hum. Virol. 1998, 1, 475–481. [Google Scholar] [PubMed]
- Daibata, M.; Taguchi, T.; Sawada, T.; Taguchi, H.; Miyoshi, I. Chromosomal transmission of human herpesvirus 6 DNA in acute lymphoblastic leukaemia. Lancet 1998, 352, 543–544. [Google Scholar] [CrossRef]
- Daibata, M.; Taguchi, T.; Taguchi, H.; Miyoshi, I. Integration of human herpesvirus 6 in a Burkitt's lymphoma cell line. Br. J. Haematol. 1998, 102, 1307–1313. [Google Scholar] [CrossRef] [PubMed]
- Nacheva, E.P.; Ward, K.N.; Brazma, D.; Virgili, A.; Howard, J.; Leong, H.N.; Clark, D.A. Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal sites. J. Med. Virol. 2008, 80, 1952–1958. [Google Scholar] [CrossRef] [PubMed]
- Watanabe, H.; Daibata, M.; Tohyama, M.; Batchelor, J.; Hashimoto, K.; Iijima, M. Chromosomal integration of human herpesvirus 6 DNA in anticonvulsant hypersensitivity syndrome. Br. J. Dermatol. 2008, 158, 640–642. [Google Scholar] [CrossRef] [PubMed]
- Troy, S.B.; Blackburn, B.G.; Yeom, K.; Caulfield, A.K.; Bhangoo, M.S.; Montoya, J.G. Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir. Clin. Infect. Dis. 2008, 47, e93–e96. [Google Scholar] [CrossRef] [PubMed]
- Barozzi, P.; Riva, G.; Vallerini, D.; Quadrelli, C.; Lagreca, I.; Eccheli, R.; Forghieri, F.; Coluccio, V.; Maccaferri, M.; Paolini, A.; et al. Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated hhv6. Clin. Microbiol. Infect. 2016, 22, 893–895. [Google Scholar] [CrossRef] [PubMed]
- Clark, D.A. Clinical and laboratory features of human herpesvirus 6 chromosomal integration. Clin. Microbiol. Infect. 2016, 22, 333–339. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Hidalgo-Bravo, A.; Zhang, E.; Cotton, V.E.; Mendez-Bermudez, A.; Wig, G.; Medina-Calzada, Z.; Neumann, R.; Jeffreys, A.J.; Winney, B.; et al. Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Res. 2014, 42, 315–327. [Google Scholar] [CrossRef] [PubMed]
- Morris, C.; Luppi, M.; McDonald, M.; Barozzi, P.; Torelli, G. Fine mapping of an apparently targeted latent human herpesvirus type 6 integration site in chromosome band 17p13.3. J. Med. Virol. 1999, 58, 69–75. [Google Scholar] [CrossRef]
- Ohye, T.; Kawamura, Y.; Inagaki, H.; Yoshikawa, A.; Ihira, M.; Yoshikawa, T.; Kurahashi, H. A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. J. Virol. Methods 2016, 228, 74–78. [Google Scholar] [CrossRef] [PubMed]
- Strenger, V.; Aberle, S.W.; Nacheva, E.P.; Urban, C. Chromosomal integration of the HHV-6 genome in a patient with nodular sclerosis Hodgkin lymphoma. Br. J. Haematol. 2013, 161, 594–595. [Google Scholar] [CrossRef] [PubMed]
- Strenger, V.; Kayser, S.; Witte, K.E.; Lassner, D.; Schwinger, W.; Jahn, G.; Urban, C.; Feuchtinger, T. Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV-6) have functionally active HHV-6 specific T-cell immunity. Clin. Microbiol. Infect. 2016, 22. [Google Scholar] [CrossRef] [PubMed]
- Torelli, G.; Barozzi, P.; Marasca, R.; Cocconcelli, P.; Merelli, E.; Ceccherini-Nelli, L.; Ferrari, S.; Luppi, M. Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo. J. Med. Virol. 1995, 46, 178–188. [Google Scholar] [CrossRef] [PubMed]
- Yagasaki, H.; Shichino, H.; Shimizu, N.; Ohye, T.; Kurahashi, H.; Yoshikawa, T.; Takahashi, S. Nine-year follow-up in a child with chromosomal integration of human herpesvirus 6 transmitted from an unrelated donor through the Japan marrow donor program. Transpl. Infect. Dis. 2015, 17, 160–161. [Google Scholar] [CrossRef] [PubMed]
- Gravel, A.; Dubuc, I.; Morissette, G.; Sedlak, R.H.; Jerome, K.R.; Flamand, L. Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris. Proc. Natl. Acad. Sci. USA 2015, 112, 8058–8063. [Google Scholar] [CrossRef] [PubMed]
- Hill, J.A.; Magaret, A.S.; Hall-Sedlak, R.; Mikhaylova, A.; Huang, M.L.; Sandmaier, B.M.; Hansen, J.A.; Jerome, K.R.; Zerr, D.M.; Boeckh, M. Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood 2017. [Google Scholar] [CrossRef] [PubMed]
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Pantry, S.N.; Medveczky, P.G. Latency, Integration, and Reactivation of Human Herpesvirus-6. Viruses 2017, 9, 194. https://doi.org/10.3390/v9070194
Pantry SN, Medveczky PG. Latency, Integration, and Reactivation of Human Herpesvirus-6. Viruses. 2017; 9(7):194. https://doi.org/10.3390/v9070194
Chicago/Turabian StylePantry, Shara N., and Peter G. Medveczky. 2017. "Latency, Integration, and Reactivation of Human Herpesvirus-6" Viruses 9, no. 7: 194. https://doi.org/10.3390/v9070194