Introduction of Chromosomally integrated human herpesvirus 6 and its clinical implications

Document Type : Systematic Review

Authors
S. Shatizadeh Malekshahi 1
K. Ketabi 2
1 Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University,Tehran, Iran
2 Department of Virology, Faculty of Medical Sciences, TarbiatModares University,Tehran, Iran
Abstract
Aims: Human herpes virus 6 (HHV-6) is a ubiquitous virus with a high rate of prevalence worldwide. In recent years, a new form of the virus genome has been identified called Chromosomally integrated HHV-6 (ciHHV-6). Further studies are required to elucidate the relation between ciHHV-6 and other clinical complications. The purpose of this study was to summarize the literature on different clinical aspects of the ciHHV-6 integration and its prevalevce in different communities.

Materials and methods: Search keywords include HHV-6, integrated genome, telomeric regions and integrated HHV-6. Scientific databases such as scopus, PubMed and google scholar with no specified start date were used for information collection.

Findings: About 1% of global populations are infected with ciHHV-6. Real-time PCR can be used to differentiate between ciHHV-6 and HHV-6 acute infection in which the viral load will be higher in ciHHV-6 compared to the acute infection. However, ciHHV-6 can be confirmed by evidence of one copy of viral DNA in hair or nail follicles. It has been shown that ciHHV-6 may disrupt the telomer stability.

Conclutions: To date, no treatment has been discovered to remove the viral genome from the host cells. Taken together, the integrated form of the HHV-6 genome could be linked to the various diseases, including heart and autoimmune diseases. But further studies are needed to find its association with other diseases in different geographic area.

Keywords

Subjects

1. Gompels UA, Nicholas J, Lawrence G, Jones M, Thomson BJ, Martin ME, et al. The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology. 1995;209(1):29-51.
2. Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue N, Pellett PE. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. Journal of virology. 1999;73(10):8040-52.
3. Ablashi D, Agut H, Berneman Z, Campadelli-Fiume G, Carrigan D, Ceccerini-Nelli L, et al. Human herpesvirus-6 strain groups: a nomenclature. Springer; 1993.
4. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science (New York, NY). 1986;234(4776):596-601.
5. Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet (London, England). 1988;1(8594):1065-7.
6. Okuno T, Takahashi K, Balachandra K, Shiraki K, Yamanishi K, Takahashi M, et al. Seroepidemiology of human herpesvirus 6 infection in normal children and adults. Journal of clinical microbiology. 1989;27(4):651-3.
7. Cameron B, Flamand L, Juwana H, Middeldorp J, Naing Z, Rawlinson W, et al. Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome. Journal of medical virology. 2010;82(10):1684-8.
8. De Bolle L, Naesens L, De Clercq E. Update on human herpesvirus 6 biology, clinical features, and therapy. Clinical microbiology reviews. 2005;18(1):217-45.
9. Ablashi DV, Devin CL, Yoshikawa T, Lautenschlager I, Luppi M, Kuhl U, et al. Review Part 3: Human herpesvirus-6 in multiple non-neurological diseases. Journal of medical virology. 2010;82(11):1903-10.
10. Yao K, Crawford JR, Komaroff AL, Ablashi DV, Jacobson S. Review part 2: Human herpesvirus-6 in central nervous system diseases. Journal of medical virology. 2010;82(10):1669-78.
11. Lusso P, Crowley RW, Malnati MS, Di Serio C, Ponzoni M, Biancotto A, et al. Human herpesvirus 6A accelerates AIDS progression in macaques. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(12):5067-72.
12. Poffenberger KL, Roizman B. 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. Journal of virology. 1985;53(2):587-95.
13. Jacob RJ, Morse LS, Roizman B. 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. Journal of virology. 1979;29(2):448-57.
14. Takahashi K, Sonoda S, Higashi K, Kondo T, Takahashi H, Takahashi M, et al. Predominant CD4 T-lymphocyte tropism of human herpesvirus 6-related virus. Journal of virology. 1989;63(7):3161-3.
15. Lusso P, Malnati M, De Maria A, Balotta C, DeRocco SE, Markham PD, et al. Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3. Journal of immunology (Baltimore, Md : 1950). 1991;147(2):685-91.
16. Yamashita N, Morishima T. HHV-6 and seizures. Herpes : the journal of the IHMF. 2005;12(2):46-9.
17. Donati D, Akhyani N, Fogdell-Hahn A, Cermelli C, Cassiani-Ingoni R, Vortmeyer A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology. 2003;61(10):1405-11.
18. Jones CM, Dunn HG, Thomas EE, Cone RW, Weber JM. Acute encephalopathy and status epilepticus associated with human herpes virus 6 infection. Developmental medicine and child neurology. 1994;36(7):646-50.
19. Dockrell DH, Paya CV. Human herpesvirus-6 and -7 in transplantation. Reviews in medical virology. 2001;11(1):23-36.
20. Lusso P, Ensoli B, Markham PD, Ablashi DV, Salahuddin SZ, Tschachler E, et al. Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature. 1989;337(6205):370-3.
21. Morissette G, Flamand L. Herpesviruses and chromosomal integration. Journal of virology. 2010;84(23):12100-9.
22. Nam Leong H, Tuke PW, Tedder RS, Khanom AB, Eglin RP, Atkinson CE, et al. The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. Journal of medical virology. 2007;79(1):45-51.
23. Hall CB, Caserta MT, Schnabel K, Shelley LM, Marino AS, Carnahan JA, et al. Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics. 2008;122(3):513-20.
24. Gompels UA, Macaulay HA. Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication. The Journal of general virology. 1995;76 ( Pt 2):451-8.
25. Ward KN, Leong HN, Nacheva EP, Howard J, Atkinson CE, Davies NW, et al. Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles. Journal of clinical microbiology. 2006;44(4):1571-4.
26. Torelli G, Barozzi P, Marasca R, Cocconcelli P, Merelli E, Ceccherini-Nelli L, et al. Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo. Journal of medical virology. 1995;46(3):178-88.
27. Nacheva EP, Ward KN, Brazma D, Virgili A, Howard J, Leong HN, et al. Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal sites. Journal of medical virology. 2008;80(11):1952-8.
28. Luppi M, Marasca R, Barozzi P, Ferrari S, Ceccherini-Nelli L, Batoni G, et al. Three cases of human herpesvirus-6 latent infection: integration of viral genome in peripheral blood mononuclear cell DNA. Journal of medical virology. 1993;40(1):44-52.
29. Hall CB, Caserta MT, Schnabel K, Shelley LM, Marino AS, Carnahan JA, et al. Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics. 2008;122(3):513-20.
30. Daibata M, Taguchi T, Taguchi H, Miyoshi I. Integration of human herpesvirus 6 in a Burkitt's lymphoma cell line. British journal of haematology. 1998;102(5):1307-13.
31. Tanaka-Taya K, Sashihara J, Kurahashi H, Amo K, Miyagawa H, Kondo K, et al. 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. Journal of medical virology. 2004;73(3):465-73.
32. Osterrieder N, Wallaschek N, Kaufer BB. Herpesvirus Genome Integration into Telomeric Repeats of Host Cell Chromosomes. Annual review of virology. 2014;1(1):215-35.
33. Gravel A, Dubuc I, Morissette G, Sedlak RH, Jerome KR, Flamand L. Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(26):8058-63.
34. Jarrett R, editor IciHHV-6 prevalence and disease associations in the generation scotland study. Proceedings of the 9th International Conference on HHV-6 and HHV-7, Boston, MA, USA; 2015.
35. Potenza L, Barozzi P, Masetti M, Pecorari M, Bresciani P, Gautheret-Dejean A, et al. Prevalence of human herpesvirus-6 chromosomal integration (CIHHV-6) in Italian solid organ and allogeneic stem cell transplant patients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(7):1690-7.
36. Hubacek P, Hrdlickova A, Spacek M, Zajac M, Muzikova K, Sedlacek P, et al. Prevalence of chromosomally integrated HHV-6 in patients with malignant disease and healthy donors in the Czech Republic. Folia microbiologica. 2013;58(1):87-90.
37. Leong HN, Tuke PW, Tedder RS, Khanom AB, Eglin RP, Atkinson CE, et al. The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. Journal of medical virology. 2007;79(1):45-51.
38. Ward KN, Thiruchelvam AD, Couto‐Parada X. Unexpected occasional persistence of high levels of HHV‐6 DNA in sera: detection of variants A and B. Journal of medical virology. 2005;76(4):563-70.
39. Lee SO, Brown RA, Razonable RR. Chromosomally integrated human herpesvirus-6 in transplant recipients. Transplant infectious disease : an official journal of the Transplantation Society. 2012;14(4):346-54.
40. Morissette G, Flamand L. Herpesviruses and chromosomal integration. Journal of virology. 2010;84(23):12100-9.
41. Martínez P, Blasco MA. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nature Reviews Cancer. 2011;11(3):161-76.
42. Tweedy J, Spyrou MA, Hubacek P, Kuhl U, Lassner D, Gompels UA. Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators. The Journal of general virology. 2015;96(Pt 2):370-89.
43. Ward KN, Leong HN, Thiruchelvam AD, Atkinson CE, Clark DA. Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis. Journal of clinical microbiology. 2007;45(4):1298-304.
44. Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, et al. The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proceedings of the National Academy of Sciences. 2010;107(12):5563-8.
45. Kaspersen MD, Larsen PB, Kofod-Olsen E, Fedder J, Bonde J, Hollsberg P. Human herpesvirus-6A/B binds to spermatozoa acrosome and is the most prevalent herpesvirus in semen from sperm donors. PloS one. 2012;7(11):e48810.
46. Kaufer BB, Flamand L. Chromosomally integrated HHV-6: impact on virus, cell and organismal biology. Curr Opin Virol. 2014;9:111-8.
47. Rotola A, Ravaioli T, Gonelli A, Dewhurst S, Cassai E, Di Luca D. U94 of human herpesvirus 6 is expressed in latently infected peripheral blood mononuclear cells and blocks viral gene expression in transformed lymphocytes in culture. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(23):13911-6.
48. Thomson BJ, Efstathiou S, Honess RW. Acquisition of the human adeno-associated virus type-2 rep gene by human herpesvirus type-6. Nature. 1991;351(6321):78-80.
49. Trempe F, Gravel A, Dubuc I, Wallaschek N, Collin V, Gilbert-Girard S, et al. Characterization of human herpesvirus 6A/B U94 as ATPase, helicase, exonuclease and DNA-binding proteins. Nucleic acids research. 2015;43(12):6084-98.
50. Wallaschek N, Gravel A, Flamand L, Kaufer BB. The putative U94 integrase is dispensable for human herpesvirus 6 (HHV-6) chromosomal integration. The Journal of general virology. 2016;97(8):1899-903.
51. Engdahl E, Dunn N, Niehusmann P, Wideman S, Wipfler P, Becker AJ, et al. Human herpesvirus 6B induces hypomethylation on chromosome 17p13. 3, correlating with increased gene expression and virus integration. Journal of virology. 2017;91(11).
52. Kreilmeier T, Mejri D, Hauck M, Kleiter M, Holzmann K. Telomere transcripts target telomerase in human cancer cells. Genes. 2016;7(8):46.
53. Wang C, Zhao L, Lu S. Role of TERRA in the regulation of telomere length. International journal of biological sciences. 2015;11(3):316-23.
54. Reig-Viader R, Garcia-Caldes M, Ruiz-Herrera A. Telomere homeostasis in mammalian germ cells: a review. Chromosoma. 2016;125(2):337-51.
55. Collin V, Flamand L. HHV-6A/B Integration and the Pathogenesis Associated with the Reactivation of Chromosomally Integrated HHV-6A/B. Viruses. 2017;9(7).
56. Lautenschlager I, Razonable RR. Human herpesvirus‐6 infections in kidney, liver, lung, and heart transplantation. Transplant International. 2012;25(5):493-502.
57. Aoki J, Numata A, Yamamoto E, Fujii E, Tanaka M, Kanamori H. Impact of human herpesvirus-6 reactivation on outcomes of allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation. 2015;21(11):2017-22.
58. de Lange T. How telomeres solve the end-protection problem. Science (New York, NY). 2009;326(5955):948-52.
59. Sfeir A, de Lange T. Removal of shelterin reveals the telomere end-protection problem. Science (New York, NY). 2012;336(6081):593-7.
60. Henaff D, Radtke K, Lippe R. Herpesviruses exploit several host compartments for envelopment. Traffic (Copenhagen, Denmark). 2012;13(11):1443-9.
61. Gruffat H, Marchione R, Manet E. Herpesvirus Late Gene Expression: A Viral-Specific Pre-initiation Complex Is Key. Frontiers in microbiology. 2016;7:869.
62. Deng H, Dewhurst S. Functional identification and analysis of cis-acting sequences which mediate genome cleavage and packaging in human herpesvirus 6. Journal of virology. 1998;72(1):320-9.
63. Kondo K, Kondo T, Okuno T, Takahashi M, Yamanishi K. Latent human herpesvirus 6 infection of human monocytes/macrophages. The Journal of general virology. 1991;72 ( Pt 6):1401-8.
64. Gilbert-Girard S, Gravel A, Artusi S, Richter SN, Wallaschek N, Kaufer BB, et al. Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration. Journal of virology. 2017;91(14).
65. Isegawa Y, Mukai T, Nakano K, Kagawa M, Chen J, Mori Y, et al. Comparison of the complete DNA sequences of human herpesvirus 6 variants A and B. Journal of virology. 1999;73(10):8053-63.
66. Martin ME, Thomson BJ, Honess RW, Craxton MA, Gompels UA, Liu MY, et al. The genome of human herpesvirus 6: maps of unit-length and concatemeric genomes for nine restriction endonucleases. The Journal of general virology. 1991;72 ( Pt 1):157-68.
67. Tweedy J, Spyrou MA, Pearson M, Lassner D, Kuhl U, Gompels UA. 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(1):19.
68. Thomson BJ, 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. Journal of virology. 1994;68(5):3007-14.
69. Pellett PE, Ablashi DV, Ambros PF, Agut H, Caserta MT, Descamps V, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Reviews in medical virology. 2012;22(3):144-55.
70. Prusty BK, Krohne G, Rudel T. Reactivation of chromosomally integrated human herpesvirus-6 by telomeric circle formation. PLoS genetics. 2013;9(12):e1004033.
71. Prusty BK, Siegl C, Hauck P, Hain J, Korhonen SJ, Hiltunen-Back E, et al. Chlamydia trachomatis infection induces replication of latent HHV-6. PloS one. 2013;8(4):e61400.
72. Kawamura Y, Hashimoto T, Miura H, Kozawa K, Yoshikawa A, Ikeda N, et al. Inherited chromosomally integrated human herpesvirus 6 and autoimmune connective tissue diseases. Journal of Clinical Virology. 2020;132:104656.
73. Miura H, Kawamura Y, Hattori F, Kozawa K, Ihira M, Ohye T, et al. Chromosomally integrated human herpesvirus 6 in the Japanese population. Journal of medical virology. 2018;90(10):1636-42.
74. Gravel A, Dubuc I, Morissette G, Sedlak RH, Jerome KR, Flamand L. Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris. Proceedings of the National Academy of Sciences. 2015;112(26):8058-63.
75. Daibata M, Taguchi T, Nemoto Y, Taguchi H, Miyoshi I. Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood. 1999;94(5):1545-9.
76. Clark DA, Nacheva EP, Leong HN, Brazma D, Li YT, Tsao EH, et al. Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. The Journal of infectious diseases. 2006;193(7):912-6.
77. Daibata M, Taguchi T, Kubonishi I, Taguchi H, Miyoshi I. Lymphoblastoid cell lines with integrated human herpesvirus type 6. Journal of human virology. 1998;1(7):475-81.
78. Daibata M, Taguchi T, Sawada T, Taguchi H, Miyoshi I. Chromosomal transmission of human herpesvirus 6 DNA in acute lymphoblastic leukaemia. Lancet (London, England). 1998;352(9127):543-4.
79. Watanabe H, Daibata M, Tohyama M, Batchelor J, Hashimoto K, Iijima M. Chromosomal integration of human herpesvirus 6 DNA in anticonvulsant hypersensitivity syndrome. The British journal of dermatology. 2008;158(3):640-2.
80. Troy SB, Blackburn BG, Yeom K, Caulfield AK, Bhangoo MS, Montoya JG. Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2008;47(12):e93-6.
81. Barozzi P, Riva G, Vallerini D, Quadrelli C, Lagreca I, Eccheli R, et al. Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV6. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2016;22(10):893-5.
82. 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. Journal of medical virology. 1999;58(1):69-75.
83. Ohye T, Kawamura Y, Inagaki H, Yoshikawa A, Ihira M, Yoshikawa T, et al. A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. Journal of virological methods. 2016;228:74-8.
84. Strenger V, Kayser S, Witte K-E, Lassner D, Schwinger W, Jahn G, et al. Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV-6) have functionally active HHV-6 specific T-cell immunity. Clinical Microbiology and Infection. 2016;22(2):209. e5-. e8.
85. Yagasaki H, Shichino H, Shimizu N, Ohye T, Kurahashi H, Yoshikawa T, et al. 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. Transplant infectious disease : an official journal of the Transplantation Society. 2015;17(1):160-1.
86. Das BB. A Neonate with Acute Heart Failure: Chromosomally Integrated Human Herpesvirus 6-Associated Dilated Cardiomyopathy. The Journal of pediatrics. 2015;167(1):188-92.e1.
87. Kühl U, Lassner D, Wallaschek N, Gross UM, Krueger GR, Seeberg B, et al. Chromosomally integrated human herpesvirus 6 in heart failure: prevalence and treatment. European journal of heart failure. 2015;17(1):9-19.
88. Saliques S, Zeller M, Lorin J, Lorgis L, Teyssier JR, Cottin Y, et al. Telomere length and cardiovascular disease. Archives of cardiovascular diseases. 2010;103(8-9):454-9.
89. Butt HZ, Atturu G, London NJ, Sayers RD, Bown MJ. Telomere length dynamics in vascular disease: a review. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2010;40(1):17-26.
90. Peddu V, Dubuc I, Gravel A, Xie H, Huang M-L, Tenenbaum D, et al. Inherited chromosomally integrated human herpesvirus 6 demonstrates tissue-specific RNA expression in vivo that correlates with an increased antibody immune response. Journal of virology. 2019;94(1).
91. Strenger V, Caselli E, Lautenschlager I, Schwinger W, Aberle SW, Loginov R, et al. Detection of HHV-6-specific mRNA and antigens in PBMCs of individuals with chromosomally integrated HHV-6 (ciHHV-6). Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2014;20(10):1027-32.
92. Hill JA, Magaret AS, Hall-Sedlak R, Mikhaylova A, Huang M-L, Sandmaier BM, et al. Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood, The Journal of the American Society of Hematology. 2017;130(8):1062-9.
93. Pantry SN, Medveczky MM, Arbuckle JH, Luka J, Montoya JG, Hu J, et al. Persistent human herpesvirus-6 infection in patients with an inherited form of the virus. Journal of medical virology. 2013;85(11):1940-6.
94. Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, et al. Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency. Clinical Infectious Diseases. 2014;59(4):545-8.
95. Gravel A, Hall CB, Flamand L. Sequence analysis of transplacentally acquired human herpesvirus 6 DNA is consistent with transmission of a chromosomally integrated reactivated virus. The Journal of infectious diseases. 2013;207(10):1585-9.
96. Ward KN. The natural history and laboratory diagnosis of human herpesviruses-6 and -7 infections in the immunocompetent. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2005;32(3):183-93.
97. Sedlak RH, Cook L, Huang ML, Magaret A, Zerr DM, Boeckh M, et al. Identification of chromosomally integrated human herpesvirus 6 by droplet digital PCR. Clinical chemistry. 2014;60(5):765-72.
98. Potenza L, Barozzi P, Torelli G, Luppi M. Translational challenges of human herpesvirus 6 chromosomal integration. Future microbiology. 2010;5(7):993-5.
99. Flamand L, Komaroff AL, Arbuckle JH, Medveczky PG, Ablashi DV. Review, part 1: Human herpesvirus-6-basic biology, diagnostic testing, and antiviral efficacy. Journal of medical virology. 2010;82(9):1560-8.
100. Caserta MT, Hall CB, Schnabel K, Lofthus G, Marino A, Shelley L, et al. Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2010;48(1):55-7.
101. Clark D. Clinical and laboratory features of human herpesvirus 6 chromosomal integration. Clinical Microbiology and Infection. 2016;22(4):333-9.
Pathobiology Reserach
Volume 23, Issue 4
June 2020
Pages 55-66