Human Herpesvirus 6: Basic Biology and Clinical Associations

  • John A. Stewart


The recognition of a new herpesvirus was announced to the world by Salahuddin et al. (1986) from the National Cancer Institute, NIH. These investigators were involved in studies of the mechanisms regulating human hematopoiesis, especially defects leading to malignancy. In these studies, mononuclear cells from patients with various lymphoproliferative disorders were established in culture, and occasionally short-lived, large, refractile cells, containing intranuclear and intracytoplasmic inclusion bodies were observed. Electron microscopic (EM) examination demonstrated herpes-type virus particles in these cultures. Unenveloped icosahedral nucleocapsids developed in the nucleus and enveloped virions were seen in cytoplasmic vesicles, cisternae and at the cell surface (Figure 1). The original six isolates, from four leukemia and lymphoma patients and two lymphadenopathy patients, were similar antigenically, but differed markedly from the other human herpesviruses. Because B-cell surface markers were detected on infected cells, the virus was called human B-lymphotropic virus (HBLV). Infection with the virus seemed rare, as only 4 of 220 serum specimens from normal donors were weakly positive by immunofluorescence antibody (IFA) testing.


Kawasaki Disease Chronic Fatigue Syndrome Human Herpesvirus Virol Method Cord Blood Lymphocyte 


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  1. Ablashi DV, Salahuddin SZ, Josephs SF, Imam F, Lusso P, Gallo RC, Hung C, Lemp J, Markham PD (1987) HBLV (or HHV-6) in human cell lines. Nature 329:207.PubMedCrossRefGoogle Scholar
  2. Ablashi DV, Joesphs SF, Buchbinder A, Hellman K, Nakamura S, Liana T, Lusso P, Kaplan M, Dahlberg J, Memon S, Imam F, Ablashi KL, Markham PD, Kramarsky B, Krueger GRF, Biberfeld Wong-Staal F, Salahuddin SZ, Gallo RC (1988) Human B-lymphotropic virus (human herpesvirus-6). J Virol Methods 21:29–48.PubMedCrossRefGoogle Scholar
  3. Agut H, Guetard D, Collandre H, Drauguet C, Montagnier L, Miclea J-M, Baurmann H, Gessain A (1988) Concomitant infection by human herpesvirus 6, HTLV-1, and HIV-2. Lancet 1:712.PubMedCrossRefGoogle Scholar
  4. Agut H, Collandre H, Aubin J-T, Guetard D, Favier V, Ingrand D, Montaignier L, Huraux J-M (1989) In vitro sensitivity of human herpesvirus-6 to antiviral drugs. Res Virol 140:219–228.PubMedCrossRefGoogle Scholar
  5. Asano Y, Suga S, Yoshikawa T, Urisu A, Yazaki T (1989a) Human herpesvirus type 6 infection (exanthem subiturn) without fever. J Pediatr 115:2264–265.Google Scholar
  6. Asano Y, Yoshikawa T, Suga S, Yazaki T, Hata T, Nagai T, Kajita Y, Ozaki T, Yoshida S (1989b) Viremia and neutralizing antibody response in infants with exanthem subiturn. J Pediatr 114:535–539.PubMedCrossRefGoogle Scholar
  7. Balachandra K, Ayuthaya PI, Auwanit W, Jayavasu C, Okuno T, Yamanishi K, Takahashi M (1989) Prevalence of antibody to human herpesvirus 6 in women and children. Microbiol Immunol 33:515–518.PubMedGoogle Scholar
  8. Balachandran N, Ameise RE, Zhou WW, Chang CK (1989) Identification of proteins specific for human herpesvirus 6 infected human T cells. J Virol 63:2835–2840.PubMedGoogle Scholar
  9. Berenberg W, Wright, S Janeway CA (1949) Roseola infantum (exanthem subitum). N Engl J Med 241:253–259.PubMedCrossRefGoogle Scholar
  10. Biberfeld P, Kramarsky B, Salahuddin SZ, Gallo RC (1987) Ultrastructural characterization of a new human B lymphotropic DNA virus (human herpesvirus 6) isolated from patients with lymphoproliferative disease. J Natl Cancer Inst 79:933–941.PubMedGoogle Scholar
  11. Biberfeld P, Petren AL, Eklund A, Lindemalm C, Barkhem T, Ekman M, Ablashi D, Salahuddin Z (1988) Human herpesvirus 6 (HHV-6, HBLV) in sarcoidosis and lymphoproliferative disorders. J Virol Methods 21:49–59.PubMedCrossRefGoogle Scholar
  12. Black JB, Sanderlin KC, Goldsmith CS, Gary HE, Lopez C, Pellett PE (1989) Growth properties of human herpesvirus 6 strain Z29. J Virol Methods 26:133–145.PubMedCrossRefGoogle Scholar
  13. Breese B (1941) Roseola infantum (exanthema subitum). NY State Med. 41:1854.Google Scholar
  14. Briggs M, Fox J, Tedder RS (1988) Age prevalence of antibody to human herpesvirus 6. Lancet 1:1058–1059.PubMedCrossRefGoogle Scholar
  15. Brown NA, Sumaya CV, Liu C-R, Ench Y, Kovacs A, Coronesi M, Kaplan MH (1988) Fall in human herpesvirus 6 seropositivity with age. Lancet 2:396.PubMedCrossRefGoogle Scholar
  16. Buchbinder A, Josephs SF, Ablashi D, Salahuddin SZ, Klotman, ME, Manak, M, Kruger, GRF, Wong-Staal F, Gallo R (1988) Polymerase chain reaction amplification and in situ hybridization for the detection of human B-lymphotropic virus. J. Virol Methods 21:191–197.CrossRefGoogle Scholar
  17. Burnstine RC, Paine RS (1959) Residual encephalopathy following roseola infantum. Am J Dis Child 98:144–152.Google Scholar
  18. Downing RG, Sewankambo N, Serwadda D, Honess R, Crawford D, Jarrett R, Griffin BE (1987) Isolation of human lymphotropic herpesviruses from Uganda. Lancet 2:390.PubMedCrossRefGoogle Scholar
  19. Efstathiou S, Gompels UA, Craxton MA, Honess RW, Ward K (1988) DNA homology between a novel human herpesvirus (HHV6) and human cytomegalovirus. Lancet 1:63–64.PubMedCrossRefGoogle Scholar
  20. Fox J, Briggs M, Tedder RS (1988) Antibody to human herpesvirus 6 in HIV-1 positive and negative homosexual men. Lancet 2:396–397.PubMedCrossRefGoogle Scholar
  21. Hellstrom B, Vahlquist B (1951) Experimental inoculation of roseola infantum. Acta Paediatrica 40:189–197.PubMedCrossRefGoogle Scholar
  22. Horvat RT, Wood C, Balachandran N (1989) Transactivation of human immunodeficiency virus promoter by human herpesvirus 6. J Virol 63:970–973.PubMedGoogle Scholar
  23. Huemer HP, Larcher C, Wachter H, Dierich MP (1989) Prevalence of antibodies to human herpesvirus 6 in human immunodeficiency virus l-seropositive and-negative intravenous drug addicts. J Infect Dis 160:549–550.PubMedCrossRefGoogle Scholar
  24. Irving WL, Cunningham AL, Keogh A, Chapman JR (1988) Antibody to both human herpesvirus 6 and cytomegalovirus. Lancet 2:630–631.PubMedCrossRefGoogle Scholar
  25. Josephs SF, Salahuddin SZ, Ablashi DV, Schachter F, Wong-Staal F, Gallo RC (1986) Genomic analysis of the human B lymphotropic virus (HBLV). Science 234:60–603.CrossRefGoogle Scholar
  26. Josephs SF, Ablashi DV, Salahuddin SZ, Kramarsky B, Franza RB, Pellett P, Buchbinder A, Memon S, Wong-Staal F, Gallo RC (1988) Molecular studies of HHV-6. J Virol Methods 21:179–190.PubMedCrossRefGoogle Scholar
  27. Kempe CH, Shaw EB, Lackson JR, Silver HK (1950) Studies on the etiology of exanthem subitum (roseola infantum). J Pediatr 37:561–568.PubMedCrossRefGoogle Scholar
  28. Kikuta H, Lu H, Matsumoto S (1989) Susceptibility of human herpesvirus 6 to acyclovir. Lancet 2:861.PubMedCrossRefGoogle Scholar
  29. Kishi M, Harada H, Takahashi M, Tanaka A, Hayashi M, Nonoyama M, Josephs SF, Buchbinder A, Schachter F, Ablashi DV, Wong-Staal F, Salahuddin SZ, Gallo RC (1988) A repeat sequence, GGGTTA, is shared by DNA of human herpesvirus 6 and Marek’s disease virus. J Virol 62:4824–4827.PubMedGoogle Scholar
  30. Knowles WA and Gardner SD (1988) High prevalence of antibody to human herpesvirus 6 and seroconversion associated with rash in two infants. Lancet 2:912–913.PubMedCrossRefGoogle Scholar
  31. Krueger GRF, Koch B, Ramon A, Ablashi DV, Salahuddin SZ, Josephs SF, Streicher HZ, Gallo RC, Habermann U (1988) Antibody prevalence to HBLV (human herpesvirus-6, HHV-6) and suggestive pathogenicity in the general population and in patients with immune deficiency syndromes. J Virol Methods 21:125–131.PubMedCrossRefGoogle Scholar
  32. Krugman S and Katz SL, (eds) (1981) Exanthema subitum (roseola infantum) In:Infectious diseases of children (Seventh Ed.) St Louis: C V Mosby Company, 59–62.Google Scholar
  33. Linde A, Dahl H, Wahren B, Fridell E, Salahuddin Z, Biberfeld P (1988) IgG antibodies to human herpesvirus-6 in children and adults both in primary Epstein-Barr virus and cytomegalovirus infections. J Virol Methods 21:117–123.PubMedCrossRefGoogle Scholar
  34. Lopez C, Pellett P, Stewart J, Goldsmith C, Sanderlin K, Black J, Warfield D, Feorino P (1988) Characteristics of human herpesvirus-6. J Infect Dis 157:1271–1273.PubMedCrossRefGoogle Scholar
  35. Lusso P, Salahuddin SZ, Ablashi DV, Gallo RC, di Marzo Veronese F, Markham PD (1987) Diverse tropism of human B-lymphotropic virus (human herpesvirus 6). Lancet 2:743–744.PubMedCrossRefGoogle Scholar
  36. Lusso P, Markham PD, Tschachler E, Veronese FdM, Salahuddin SZ, Ablashi DV, Pahwa S, Krohn K, Gallo RC (1988) In vitro cellular tropism of Human B-lymphotropic virus (human herpesvirus-6). J Exp Med 167:1659–1670.PubMedCrossRefGoogle Scholar
  37. Lusso P, Ensoli B, Markham PD, Ablashi DV, Salahuddin SZ, Tschachler E, Wong-Staal F, Gallo RC (1989) Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV6. Nature 337:370–373.PubMedCrossRefGoogle Scholar
  38. Morris DJ, Littler E, Jordan D, Arrand JR (1988) Antibody responses to human herpesvirus 6 and other herpesviruses. Lancet 2:1425–1426.CrossRefGoogle Scholar
  39. Morris DJ, Littler E, Arrand JR, Jordan D, Mallick NP, Johnson RWG (1989) Human herpesvirus 6 infection in renal-transplant recipients. Lancet 1:1560–1561.Google Scholar
  40. Niederman JC, Liu C-R, Kaplan MH, Brown NA (1988) Clinical and serological features of human herpesvirus 6 infection in three adults. Lancet 2:817–819.PubMedCrossRefGoogle Scholar
  41. Okuno T, Higashi K, Shiraki K, Yamanishi K, Takahashi M, Kokado Y, Ishibashi M, Takahara S, Sonoda T, Tanaka K, Baba K, Yabuuchi H, Kurata T (1989a) Human herpesvirus 6 (HHV-6) infection in renal transplantation. Transplantation (in press).Google Scholar
  42. Okuno T, Takahashi K, Balachandra K, Shiraki K, Yamanishi K, Takahashi M, Baba K (1989b) Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol 27:651–653.PubMedGoogle Scholar
  43. Pellett PE, Lindquester GJ, Feorino P, Lopez C (1990) Genomic heterogeneity of human herpesvirus 6 isolates. In: Immunobiology and Prophylaxis of Human Herpesvirus Infection (eds) Lopez C, Mori R, Roizman B, Whitley R. New York: Plenum Press (in press).Google Scholar
  44. Pietroboni GR, Harnett GB, Farr TJ, Bucens MR (1988) Human herpes virus type 6 (HHV-6) and its in vitro effect on human immunodeficiency virus (HIV). J Clin Pathol 41:1310–1312.PubMedCrossRefGoogle Scholar
  45. Russler SK, Tapper MA, Carrigan DR (1989) Susceptibility of human herpesvirus 6 to acyclovir and gancyclovir. Lancet 2:382.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. Saxinger C, Polesky H, Eby N, Grufferman S, Murphy R, Tegtmeier G, Parekh V, Memon S, Hung C (1988) Antibody reactivity with HBLV (HHV-6) in U.S. populations. J Virol Methods 21:199–208.PubMedCrossRefGoogle Scholar
  48. Shiraki K, Okuno T, Yamanishi K, Takahashi M (1989) Virion and nonstructural polypeptides of human herpesvirus-6. Virus Research 13:173–178.PubMedCrossRefGoogle Scholar
  49. Spira TJ, Bozeman LH, Sanderlin KC, Warfield D, Feorino PM, Holman R, Kaplan JE, Fishbein DB, Lopez C (1990) Lack of correlation between human herpesvirus 6 infection and the course of human immunodeficiency virus infection. J Infect Dis 161: 567–570.PubMedCrossRefGoogle Scholar
  50. Streicher HZ, Hung CL, Ablashi DV, Hellman K, Saxinger C, Fullen J, Salahuddin SZ (1988) In vitro inhibition of human herpesvirus-6 by phosphono-formate. J Virol Methods 21:301–304.PubMedCrossRefGoogle Scholar
  51. Suga S, Yoshikawa T, Asano Y, Yazaki T, Hirata S (1989) Human herpesvirus-6 infection (exanthem subitum) without rash. Pediatrics 83:1003–1006.PubMedGoogle Scholar
  52. Takahashi K, Sonoda S, Kawakami K, Miyata K, Oki T, Nagata T (1988) Human herpesvirus 6 and exanthem subitum. Lancet 1:1463.PubMedCrossRefGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. Tedder RS, Briggs M, Cameron CH, Honess R, Robertson D, Whittle H (1987) A novel lymphotropic herpesvirus. Lancet 2:390–392.PubMedCrossRefGoogle Scholar
  55. Ueda K, Kusuhara K, Hirose M, Okada K, Miyazaki C, Tokugawa K, Nakayama M, Yamanishi K (1989) Exanthem subitum and antibody to human herpesvirus-6. J Infect Dis 159:750–752.PubMedCrossRefGoogle Scholar
  56. Ward KN, Gray JJ, Efstathiou S (1989) Brief report: Primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. J Med Virol 28:69–72.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. Yoshida M, Uno F, Bai ZL, Yamada M, Nii S, Sata T, Kurata T, Yamanishi K, Takahashi M (1989) Electron microscopic study of a herpes-type virus isolated from an infant with exanthem subitum. Microbiol Immunol 33:147–154.PubMedGoogle Scholar
  59. Yoshida T, Yoshiyama H, Suzuki E, Harada S, Yanagi K, Yamamoto N (1989) Immune response of exanthema subitum to human herpesvirus type 6 (HHV-6) polypeptides. J Infect Dis 160:901–902.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • John A. Stewart
    • 1
  1. 1.Viral Exanthems and Herpesviruses Branch, Division of Viral DiseasesCenters for Disease ControlAtlantaUSA

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