Review, part 1: Human herpesvirus-6 - Basic biology, diagnostic testing, and antiviral efficacy

Journal of Medical Virology

Volumn 82, Issue 9, 2010, Pages 1560-1568

  Flamand, Louis ^a   Komaroff, Anthony L ^b   Arbuckle, Jesse H ^c   Medveczky, Peter G ^c   Ablashi, Dharam V ^d  

^a UNIVERSITÉ LAVAL   (Canada)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c UNIVERSITY OF SOUTH FLORIDA   (United States)

^d The HHV 6 Foundation   (United States)

Author keywords

Biology; Diagnostics; Efficacy; Human herpesvirus

Indexed keywords

2 AMINO 7 [(1,3 DIHYDROXY 2 PROPOXY)METHYL]PURINE; 9 (3 HYDROXY 2 PHOSPHONOMETHOXYPROPYL)ADENINE; 9 [1,2 BIS(HYDROXYMETHYL)CYCLOPROPYLMETHYL]GUANINE; ACICLOVIR; ANTIVIRUS AGENT; ARTESUNATE; CIDOFOVIR; CMV 423; CYCLOPROPANE DERIVATIVE; CYCLOPROPAVIR; CYTOMEGALOVIRUS ANTIBODY; FOSCARNET; GANCICLOVIR; SULFONE DERIVATIVE; UNCLASSIFIED DRUG; VALGANCICLOVIR;

BIOLOGY; CYTOMEGALOVIRUS INFECTION; DIAGNOSTIC PROCEDURE; DRUG ACTIVITY; DRUG EFFICACY; GENE EXPRESSION; HUMAN; HUMAN HERPESVIRUS 6; HUMAN HERPESVIRUS 6 INFECTION; IMMUNOMODULATION; PATHOGENESIS; REVIEW; VIRUS DETECTION; VIRUS GENE; VIRUS INFECTION; VIRUS REPLICATION; VIRUS RESISTANCE; VIRUS STRAIN;

ANTIBODIES, VIRAL; ANTIGENS, VIRAL; ANTIVIRAL AGENTS; DNA, VIRAL; HERPESVIRUS 6, HUMAN; HUMANS; POLYMORPHISM, GENETIC; RECEPTORS, VIRUS; ROSEOLOVIRUS INFECTIONS; VIRUS ACTIVATION; VIRUS LATENCY;

HERPESVIRIDAE; HUMAN HERPESVIRUS 6;

EID: 77956574174     PISSN: 01466615     EISSN: 10969071     Source Type: Journal    
DOI: 10.1002/jmv.21839     Document Type: Review

References (84)

1. Ablashi D, Devin C, Yoshikawa T, Lautenschlager I, Luppi M, Komaroff A. 2010. Human herpesvirus-6 in non-neurological diseases. J Med Virol (in press).
2. Achour A, Malet I, Le Gal F, Dehee A, Gautheret-Dejean A, Bonnafous P, Agut H. 2008. Variability of gB and gH genes of human herpesvirus-6 among clinical specimens. J Med Virol 80:1211-1221. (Pubitemid 351706000)
3. 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.
4. Akkapaiboon P, Mori Y, Sadaoka T, Yonemoto S, Yamanishi K. 2004. Intracellular processing of human herpesvirus 6 gylcoproteins Q1 and Q2 into tetrameric complexes expressed on the viral envelope. J Virol 78:7969-7983. (Pubitemid 38944282)
5. Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, Lund TC, Tolar J, DeMeirleir K, Montoya JG, Komaroff AL, Ambros 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.
6. Bonnafous P, Naesens L, Petrella S, Gautheret-Dejean A, Boutolleau D, Sougakoff W, Agut H. 2007. Different mutations in the HHV-6 DNA polymerase gene accounting for resistance to foscarnet. Antivir Ther 12:877-888. (Pubitemid 47492557)
7. Bonnafous P, Boutolleau D, Naesens L, Deback C, Gautheret-Dejean A, Agut H. 2008. Characterization of a cidofovir-resistant HHV-6 mutant obtained by in vitro selection. Antiviral Res 77:237-240.
8. Braun DK, Dominguez G, Pellett PE. 1997. Human herpesvirus 6. Clin Microbiol Rev 10:521-567.
9. 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. (Pubitemid 27508830)
10. Catusse J, Parry CM, Dewin DR, Gompels UA. 2007. Inhibition of HIV-1 infection by viral chemokine U83A via high-affinity CCR5 interactions that block human chemokine-induced leukocyte chemotaxis and receptor internalization. Blood 109:3633-3639. (Pubitemid 46641709)
11. Catusse J, Spinks J, Mattick C, Dyer A, Laing K, Fitzsimons C, Smit MJ, Gompels UA. 2008. Immunomodulation by herpesvirus U51A chemokine receptor via CCL5 and FOG-2 down-regulation plus XCR1 and CCR7 mimicry in human leukocytes. Eur J Immunol 38:763-777.
12. Clark DA, Ward KN. 2008. Importance of chromosomally integrated HHV-6A and -6B in the diagnosis of active HHV-6 infection.Herpes 15:28-32.
13. Clark DA, Nacheva EP, Leong HN, Brazma D, Li YT, Tsao EH, Buyck HC, Atkinson CE, Lawson HM, Potter MN, Griffiths PD. 2006a. Transmission of integrated human herpesvirus 6 through stem cell transplantation: Implications for laboratory diagnosis. J Infect Dis 193:912-916.
14. Clark DA, Tsao EHF, Leong HN, Ward KN, Nacheva EP, Griffiths PD. 2006b. Reply to Boutolleau et al. and Luppi et al. J Infect Dis 194:1021-1023.
15. Daibata MTT, Taguchi H, Miyoshi I. 1998. Integration of human herpesvirus 6 in Burkitt's lymphoma cell line. Br J Haematol 102:1307-1313. (Pubitemid 28435217)
16. Daibata M, Taguchi T, Nemoto Y, Taguchi H, Miyoshi I. 1999. Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood 94:1545-1549. (Pubitemid 29411303)
17. De Bolle L, Andrei G, Snoeck R, Zhang Y, Van Lommel A, Otto M, Bousseau A, Roy C, De Clercq E, Naesens L. 2004. Potent, selective and cell-mediated inhibition of human herpesvirus 6 at an early stage of viral replication by the non-nucleoside compound CMV423. Biochem Pharmacol 67:325-336. (Pubitemid 38112763)
18. 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. (Pubitemid 40170670)
19. DeClerq F, Naesens L, DeBolle L, Schols D, Zhang Y, Neyts J. 2001. Antiviral agents active against human herpesviruses HHV-6, HHV-7, and HHV-8. Rev Med Virol 11:381-395. (Pubitemid 34024256)
20. de Lange T. 2004. T-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5:323-329.
21. 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. (Pubitemid 23232759)
22. Dewin DR, Catusse J, Gompels UA. 2006. Identification and characterization of U83A viral chemokine, a broad and potent beta-chemokine agonist for human CCRs with unique selectivity and inhibition by spliced isoform. J Immunol 176:544-556. (Pubitemid 43023302)
23. Fitzsimons CP, Gompels UA, Verzijl D, Vischer HF, Mattick C, Leurs R, Smit MJ. 2006. Chemokine-directed trafficking of receptor stimulus to different g proteins: Selective inducible and constitutive signaling by human herpesvirus 6-encoded chemokine receptor U51.Mol Pharmacol 69:888-898.
24. Flamand L, Gravel A, Boutolleau D, Alvarez-Lafuente R, Jacobson S, Malnati MS, Kohn D, Tang YW, Yoshikawa T, Ablashi D. 2008. Multicenter comparison of PCR assays for detection of human herpesvirus 6 DNA in serum. J Clin Microbiol 46:2700-2706.
25. Galarraga MC, Gomez E, de Ona M, Rodriguez A, Laures A, Boga JA, Fernandez JA, Melon S. 2005. Ganciclovir prophylaxis and beta-herpesvirus in renal transplant recipients. Transpl Int 18:1016-1017. (Pubitemid 41726803)
26. Glosson NL, Hudson AW. 2007. Human herpesvirus-6A and -6B encode viral immunoevasins that downregulate class I MHC molecules. Virology 365:125-135.
27. Gravel A, Gosselin J, Flamand L. 2002. Human Herpesvirus 6 immediate-early 1 protein is a sumoylated nuclear phosphoprotein colocalizing with promyelocytic leukemia protein-associated nuclear bodies. J Biol Chem 277:19679-19687. (Pubitemid 34967483)
28. Gravel A, Dion V, Cloutier N, Gosselin J, Flamand L. 2004. Characterization of human herpesvirus 6 variant B immediate-early 1 protein modifications by small ubiquitin-related modifiers. J Gen Virol 85:1319-1328. (Pubitemid 38659796)
29. Greenstone HL, Santoro F, Lusso P, Berger EA. 2002. Human herpesvirus 6 and measles virus employ distinct CD46 domains for receptor function. J Bikol Chem 277:39112-39118. (Pubitemid 35190878)
30. 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.
31. Harma M, Hockerstedt K, Lyytikainen O, Lautenschlager I. 2006. HHV-6 and HHV-7antigenemia related to CMV infection after liver transplantation. J Med Virol 78:800-805.
32. Henckaerts E, Dutheil N, Zeltner N, Kattman S, Kohlbrenner E, Ward P, Clement 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.
33. Henson JD, Neumann AA, Yeager TR, Reddel RR. 2002. Alternative lengthening of telomeres in mammalian cells. Oncogene 21:598-610. (Pubitemid 34146260)
34. Huang H, Li Y, Sadaoka T, Tang H, Yamamoto T, Yamanishi K, Mori Y. 2006. Human herpesvirus 6 envelope cholesterol is required for virus entry. J Gen Virol 87:277-285.
35. Hubacek P, Muzikova K, Hrdlickova A, Cinek O, Hyncicova K, Hrstkova H, Sedlacek P, Stary J. 2009a. Prevalence of HHV-6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic. J Med Virol 81:258-263.
36. Hubacek P, Virgili A, Ward KN, Pohlreich D, Keslova P, Goldova B, Markova M, Zajac M, Cinek O, Nacheva EP, Sedlacek P, Cetkovsky P. 2009b. HHV-6 DNA throughout the tissues of two stem cell transplant patients with chromosomally integrated HHV-6 and fatal CMV pneumonitis. Br J Haematol 145:394-398.
37. 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.
38. Isegawa Y, Hara J, Amo K, Osugi Y, Takemoto M, Yamanishi K, Fukunaga R, Shibata M, Ohshima A, Horiguchi Y, Sugimoto N. 2009. Human herpesvirus 6 ganciclovir-resistant strain with amino acid substitutions associated with the death of an allogeneic stem cell transplant recipient. J Clin Virol 44:15-19.
39. Jaworska J, Gravel A, Fink K, Grandvaux N, Flamand L. 2007. Inhibition of transcription of the beta interferon gene by the human herpesvirus 6 immediate-early 1 protein. J Virol 81:5737-5748.
40. Kern ER, Kushner NL, Hartine CB, Williams-Aziz SL, Harden EA, Zhou S, Zemlicka J, Prichard MN. 2005. In vitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication. Antimicrob Agents Chemother 49:1039-1045.
41. Leong HN, Tuke PW, Tedder RS, Khanom AB, Eglin RP, Atkinson CE, Ward KN, Griffiths 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.
42. Ljungman P, de la Camara R, Cordonnier C, Einsele H, Engelhard D, Reusser P, Styczynski J, Ward K. 2008. Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant 42:227-240.
43. 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.
44. 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.
45. Milbradt J, Auerochs S, Korn K, Marschall M. 2009. Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate. J Clin Virol 46:24-28.
46. Mirandola P, Menegazzi P, Merighi S, Ravaioli T, Cassai E, Di Luca D. 1998. Temporal mapping of transcripts in herpesvirus 6 variants. J Virol 72:3837-3844.
47. Mori Y, Yang X, Akkapaiboon P, Okuno T, Yamanishi K. 2003. Human herpesvirus 6 variant A glycoprotein H-glycoprotein L-glycoprotein Q complex associates with human CD46. J Virol 77:4992-4999.
48. 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.
49. Naesens L, Bonnafous P, Agut H, DeClerq E. 2006a. Antiviral activity of diverse classes of broad-acting agents and natural compunds in HHV-6-infected lymphoblasts. J Clin Virol 37(Suppl 1):S-69-S75.
50. Naesens L, Stephens CE, Andrei G, Loregian A, DeBolle L, Snoeck R, Sowell JW, DeClerq E. 2006b. Antiviral properties of new arylsufione deriatives with activity against human beta-herpesviruses. Antiviral Res 72:60-67.
51. Oster B, Hollsberg P. 2002. Viral gene expression patterns in human herpesvirus 6B-infected T cells. J Virol 76:7578-7586.
52. Oster B, Bundgaard B, Hupp TR, Hollsberg P. 2008a. Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway. J Gen Virol 89:87-96.
53. Oster B, Kofod-Olsen E, Bundgaard B, Hollsberg P. 2008b. Restriction of human herpesvirus 6B replication by p53. J Gen Virol 89:1106-1113.
54. Parcells MS, Arumugaswami V, Prigge JT, Pandya K, Dienglewicz RL. 2003. Marek's disease virus reactivation from latency: Changes in gene expression at the origin of replication. Poult Sci 82:893-898.
55. Pederson SM, Oster B, Bundgaard B, Holisberg P. 2006. Induction of cell-cell fusion from without by human herpesvirus 68. J Virol 80:9916-9920.
56. Rapp JC, Krug LT, Inoue N, Dambaugh TR, Pellett PE. 2000. U94, the human herpesvirus 6 homolog of the parvovirus nonstructural gene, is highly conserved among isolates and is expressed at low mRNA levels as a spliced transcript. Virology 268:504-516.
57. Razonable RR, Brown RA, Humar A, Covington E, Alecock E, Paya CV. 2005. Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease. J Infect Dis 192:1331-1339. (Pubitemid 41401145)
58. Reddel RR. 2000. The role of senescence and immortalization in carcinogenesis. Carcinogenesis 21:477-484.
59. Rivas AL, Fabricant J. 1988. Indications of immunodepression in chickens infected with various strains of Marek's disease virus. Avian Dis 32:1-8.
60. 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.
61. 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.
62. 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.
63. Santoro F, Kennedy PE, Locatelli G, Mainati MS, Berger EA, Lusso P. 1999. CD46 is a cellular receptor for human herpesvirus 6. Cell 99:817-827.
64. Schleimann MH, Moller JM, Kofod-Olsen E, Hollsberg P. 2009. Direct Repeat 6 from human herpesvirus-6B encodes a nuclear protein that forms a complex with the viral DNA processivity factor p41. PLoS ONE 4:e7457.
65. Shay JW, Bacchetti S. 1997. A survey of telomerase activity in human cancer. Eur J Cancer 33:787-791.
66. Sjahril R, Isegawa Y, Tanaka T, Nakano K, Yoshikawa T, Asano Y, Ohshima A, Yamanishi K, Sugimoto N. 2009. Relationship between U83 gene variation in human herpesvirus 6 and secretion of the U83 gene product. Arch Virol 154:273-283.
67. Sullivan BM, Coscoy L. 2008. Downregulation of the T-cell receptor complex and impairment of T-cell activation by human herpesvirus 6 u24 protein. J Virol 82:602-608.
68. Tai AK, Luka J, Ablashi D, Huber BT. 2009. HHV-6A infection induces expression of HERV-K18-encoded superantigen. J Clin Virol 46:47-48.
69. Takemoto M, Koike M, Mori Y, Yonemoto S, Sasamoto Y, Kondo K, Uchiyama Y, Yamanishi K. 2005. Human herpesvirus 6 open reading frame U14 protein and cellular p53 interact with each other and are contained in the virion. J Virol 79:13037-13046.
70. Tanaka-Taya K, Sashihara J, Kurahashi H, Amo K, Miyagawa H, Kondo K, Okada S, Yamanishi 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.
71. Tang H, Kawabata A, Takemoto M, Yamanishi K, Mori Y. 2008. Human herpesvirus-6 infection induces the reorganization of membrane microdomains in target cells, which are required for virus entry. Virology 378:265-271.
72. 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.
73. 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.
74. Tomaska L, Nosek J, Kramara J, Griffith JD. 2009. Telomeric circles: Universal players in telomere maintenance? Nat Struct Mol Biol 16:1010-1015.
75. Tomoiu A, Gravel A, Flamand L. 2006a. Mapping of human herpesvirus 6 immediate-early 2 protein transactivation domains. Virology 354:91-102.
76. Tomoiu A, Gravel A, Tanguay RM, Flamand L. 2006b. Functional interaction between human herpesvirus 6 immediate-early 2 protein and ubiquitin-conjugating enzyme 9 in the absence of sumoylation. J Virol 80:10218-10228.
77. 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.
78. 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.
79. Tsao EH, Kellam P, Sin CS, Rasaiyaah J, Griffiths PD, Clark DA. 2009. Microarray-based determination of the lytic cascade of human herpesvirus 6B. J Gen Virol 90:2581-2591.
80. Turcanova VL, Bundgaard B, Hollsberg P. 2009. Human herpesvirus- 6B induces expression of the human endogenous retrovirus K18-encoded superantigen. J Clin Virol 46:15-19.
81. Ward KN, Leong HN, Nacheva EP, Howard J, Atkinson CE, Davies NW, Griffiths 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.
82. Ward KN, Leong HN, Thiruchelvam AD, Atkinson CE, Clark DA. 2007. 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. J Clin Microbiol 45:1298-1304.
83. Yao K, Crawford J, Komaroff A, Ablashi D, Jacobson J. 2010. Human herpesvirus-6 in central nervous system diseases. J Med Virol (in press).
84. Yeo WM, Isegawa Y, Chow VT. 2008. The U95 protein of human herpesvirus 6B interacts with human GRIM-19: Silencing of U95 expression reduces viral load and abrogates loss of mitochondrial membrane potential. J Virol 82:1011-1020.