Human Herpesviruses‐6 and ‐7 (HHV‐6A, HHV‐6B and HHV‐7)


Infection with human herpesviruses‐6 and ‐7 (HHV‐6/7) is universal in human populations. Early studies did not distinguish between the two virus species, HHV‐6A and HHV‐6B. No disease has been causally linked to HHV‐6A, but HHV‐6B and HHV‐7 are established as a cause of febrile illness in early childhood that is sometimes accompanied by fits. HHV‐6B can also cause encephalitis after haematopoietic stem cell transplant.

Chromosomally integrated HHV‐6 (either A or B) is a condition in which the complete viral genome is present in every nucleated cell in the body; it occurs in a minority of people and is vertically transmitted. Lack of recognition of this phenomenon has led to the misdiagnosis of active infection and inappropriate use of antiviral therapy. An important unresolved question is whether integrated virus is a cause of disease.

Key Concepts:

  • The term HHV‐6 covers two herpesvirus species, HHV‐6A and HHV‐6B.

  • HHV‐6A is not known to cause any disease.

  • HHV‐6B primary infection may cause fever, rash and febrile fits.

  • HHV‐6B reactivation may cause encephalitis in haematopoietic stem cell transplant recipients.

  • HHV‐7 primary infection may cause fever, rash and febrile fits.

  • Chromosomal integration of HHV‐6 (CIHHV‐6) involves either HHV‐6A or HHV‐6B and is always telomeric.

  • CIHHV‐6 occurs in approximately 1% of the human population and is vertically transmitted.

  • A lack of understanding of the phenomenon of CIHHV‐6 has led to misdiagnosis of disease and inappropriate antiviral treatment.

  • Whether or not CIHHV‐6 can reactivate in vivo and cause disease is currently unknown.

Keywords: HHV‐6A; HHV‐6B; CIHHV‐6; chromosomal integration; telomeres; encephalitis; febrile convulsions; febrile fits; status epilepticus

Figure 1.

Electron micrographs of HHV‐6 particles: (a) Negative contrast preparation showing three viruses that appear opaque and structureless because the virus envelope remained intact during preparation and was not penetrated by the contrast stain; three additional viruses (centre and below) have envelopes that were damaged during preparation, allowing the stain to enter and reveal the central icosahedral capsid (125 nm in diameter) within. The icosahedral capsids appear hexagonal in outline and short tubular capsomeres can be seen at their edges. (b) Ultrathin section through numerous enveloped viruses. The nucleic acid inner core is clearly visible within each capsid (diameter 125 nm), which is in turn surrounded by the dense tegument below the envelope with its viral glycoproteins.

Figure 2.

HHV‐6 cytopathic effect (CPE). Cultured peripheral blood lymphocytes showing the characteristic CPE induced by HHV‐6 infection: (a) Mock‐infected cells and (b) HHV‐6‐infected ballooning cells at the bottom of cell clump. Reproduced with permission from Di Luca et al. . © Elsevier.

Figure 3.

HHV‐6 and HHV‐7 antibodies in British children: (a) Prevalence of HHV‐6 IgG. Maternally acquired antibody dies away by approximately 26 weeks (6 months) after which natural primary infection begins, affecting all children by 104 weeks (2 years) and (b) comparison of HHV‐6 and HHV‐7 infection in British children in relation to age. Prevalence=number of cases with past infection/number with past infection plus uninfected ×100. Reproduced with permission from Ward . © Elsevier.

Figure 4.

HHV‐6 integration at the telomeric end of the short arm of chromosome 17 as mapped by FISH. Example of a dividing cell showing an HHV‐6 FISH green signal seen as two green dots at the tip of the short arm of one homologue of chromosome 17 demonstrating the location of the integrated virus on the sister chromatids. An arrow points to the other homologue of chromosome 17. The red signals are from locus‐specific probes for 9q34.3 (the telomeric region of the long arm) on both homologues of chromosome 9. Photomicrograph kindly supplied by Dr E Nacheva. Methods and materials used for FISH analysis were from Nacheva et al..

Figure 5.

Transmission of CIHHV‐6 from parent to child: pedigrees of four Japanese families. Individuals with CIHHV‐6 are shown in black, whereas those not so affected are shown in white. □, male; ○, female. Adapted with permission from Tanaka‐Taya et al..

Figure 6.

Virological features of primary HHV‐6 and HHV‐7 infections. Reproduced with permission from Ward . © Elsevier.



Agut H (2011) Deciphering the clinical impact of acute human herpesvirus 6 (HHV‐6) infections. Journal of Clinical Virology 52: 164–171.

Andre‐Garnier E, Milpied N, Boutolleau D et al. (2004) Reactivation of human herpesvirus 6 during ex vivo expansion of circulating CD34+ haematopoietic stem cells. Journal of General Virology 85: 3333–3336.

Challoner PB, Smith KT, Parker JD et al. (1995) Plaque‐associated expression of human herpesvirus 6 in multiple sclerosis. Proceedings of the National Academy of Sciences of the USA 92: 7440–7444.

Chuh A, Chan H and Zawar V (2004) Pityriasis rosea – evidence for and against an infectious aetiology. Epidemiology and Infection 132: 381–390.

Clark DA, Nacheva EP, Leong HN et al. (2006) Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. Journal of Infectious Diseases 193: 912–916.

Desachy A, Ranger‐Rogez S, Francois B et al. (2001) Reactivation of human herpesvirus type 6 in multiple organ failure syndrome. Clinical Infectious Diseases 32: 197–203.

Di Luca D, Katsafanas G, Schirmer EC, Balachandran N and Frenkel N (1990) The replication of viral and cellular DNA in human herpesvirus 6‐infected cells. Virology 175: 199–210.

Drobyski WR, Knox KK, Majewski D and Carrigan DR (1994) Brief report: fatal encephalitis due to variant B human herpesvirus‐6 infection in a bone marrow‐transplant recipient. New England Journal of Medicine 330: 1356–1360.

Epstein LG, Shinnar S, Hesdorffer DC et al. (2012) Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 53: 1481–1488.

Hall CB, Caserta MT, Schnabel KC et al. (2004) Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). Journal of Pediatrics 145: 472–477.

Hall CB, Caserta MT, Schnabel K et al. (2008) Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics 122: 513–520.

Hall CB, Long CE, Schnabel KC et al. (1994) Human herpesvirus‐6 infection in children. A prospective study of complications and reactivation. New England Journal of Medicine 331: 432–438.

Higashimoto Y, Ohta A, Nishiyama Y et al. (2012) Development of a human herpesvirus 6 species‐specific immunoblotting assay. Journal of Clinical Microbiology 50: 1245–1251.

Hubacek P, Hyncicova K, Muzikova K et al. (2007a) Disappearance of pre‐existing high HHV‐6 DNA load in blood after allogeneic SCT. Bone Marrow Transplantation 40: 805–806.

Hubacek P, Maalouf J, Zajickova M et al. (2007b) Failure of multiple antivirals to affect high HHV‐6 DNAaemia resulting from viral chromosomal integration in a case of severe aplastic anaemia. Haematologica 92(10): e98–e100.

Hubacek P, Muzikova K, Hrdlickova A et al. (2009a) Prevalence of HHV‐6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic. Journal of Medical Virology 81: 258–263.

Hubacek P, Virgili A, Ward KN et al. (2009b) HHV‐6 DNA throughout the tissues of two stem cell transplant patients with chromosomally integrated HHV‐6 and fatal CMV pneumonitis. British Journal of Haematology 145: 394–398.

Kondo K, Kondo T, Okuno T, Takahashi M and Yamanishi K (1991) Latent human herpesvirus 6 infection of human monocytes/macrophages. Journal of General Virology 72: 1401–1408.

Lau YL, Peiris M, Chan GC et al. (1998) Primary human herpes virus 6 infection transmitted from donor to recipient through bone marrow infusion. Bone Marrow Transplantation 21: 1063–1066.

Lee SO, Brown RA and Razonable RR (2012) Chromosomally integrated human herpesvirus‐6 in transplant recipients. Transplant Infectious Disease 14: 346–354.

Leong HN, Tuke PW, Tedder RS et al. (2007) The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. Journal of Medical Virology 79: 45–51.

Lo YM, Lau TK, Chan LY, Leung TN and Chang AM (2000) Quantitative analysis of the bidirectional fetomaternal transfer of nucleated cells and plasma DNA. Clinical Chemistry 46: 1301–1309.

Luppi M, Marasca R, Barozzi P et al. (1993) Three cases of human herpesvirus‐6 latent infection: integration of viral genome in peripheral blood mononuclear cell DNA. Journal of Medical Virology 40: 44–52.

McCullers JA, Lakeman FD and Whitley RJ (1995) Human herpesvirus 6 is associated with focal encephalitis. Clinical Infectious Diseases 21: 571–576.

Miyake F, Yoshikawa T, Sun H et al. (2006) Latent infection of human herpesvirus 7 in CD4(+) T lymphocytes. Journal of Medical Virology 78: 112–116.

Nacheva EP, Ward KN, Brazma D et al. (2008) Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal sites. Journal of Medical Virology 80: 1952–1958.

Oliveira SA, Turner DJ, Knowles W et al. (2003) Primary human herpesvirus‐6 and ‐7 infections, often coinciding, misdiagnosed as measles in children from a tropical region of Brazil. Epidemiology and Infection 131: 873–879.

Potenza L, Luppi M, Barozzi P et al. (2008) HHV‐6A in syncytial giant‐cell hepatitis. New England Journal of Medicine 359: 593–602.

Salahuddin SZ, Ablashi DV, Markham PD et al. (1986) Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234: 596–601.

Santoro F, Kennedy PE, Locatelli G et al. (1999) CD46 is a cellular receptor for human herpesvirus 6. Cell 99: 817–827.

Scheurer ME, Pritchett JC, Amirian ES et al. (2012) HHV‐6 encephalitis in umbilical cord blood transplantation: a systematic review and meta‐analysis. Bone Marrow Transplant, doi: 10.1038/bmt.2012.180.

Seeley WW, Marty FM, Holmes TM et al. (2007) Post‐transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 69: 156–165.

Tanaka K, Kondo T, Torigoe S et al. (1994) Human herpesvirus 7: another causal agent for roseola (exanthem subitum). Journal of Pediatrics 125: 1–5.

Tanaka‐Taya K, Sashihara J, Kurahashi H et al. (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. Journal of Medical Virology 73: 465–473.

Ward KN (2005) The natural history and laboratory diagnosis of human herpesviruses‐6 and ‐7 infections in the immunocompetent. Journal of Clinical Virology 32: 183–193.

Ward KN, Andrews NJ, Verity CM, Miller E and Ross EM (2005a) Human herpesviruses‐6 and ‐7 each cause significant neurological morbidity in Britain and Ireland. Archives of Disease in Childhood 90: 619–623.

Ward KN, Bryant NJ, Andrews NJ et al. (2007a) Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Pediatrics 120: 314–321.

Ward KN and Clark DA (2009) Roseoloviruses: human herpesviruses 6A, 6B and 7. In: Zuckerman A, Banatvala J, Schoub B, Griffiths P and Mortimer P (eds) Principles and Practice of Clinical Virology, pp. 223–244. Chichester, UK: Wiley‐Blackwell.

Ward KN, Gray JJ and Efstathiou S (1989) Brief report: primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. Journal of Medical Virology 28: 69–72.

Ward KN, Kalima P, MacLeod KM and Riordan T (2002) Neuroinvasion during delayed primary HHV‐7 infection in an immunocompetent adult with encephalitis and flaccid paralysis. Journal of Medical Virology 67: 538–541.

Ward KN, Leong HN, Nacheva EP et al. (2006) 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 44: 1571–1574.

Ward KN, Leong HN, Thiruchelvam AD, Atkinson CE and Clark DA (2007b) 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 45: 1298–1304.

Ward KN, Thiruchelvam AD and Couto‐Parada X (2005b) Unexpected occasional persistence of high levels of HHV‐6 DNA in sera; detection of variants A and B. Journal of Medical Virology 76: 563–570.

Ward KN, Turner DJ, Couto Parada X and Thiruchelvam AD (2001) Use of immunoglobulin G antibody avidity for differentiation of primary human herpesvirus 6 and 7 infections. Journal of Clinical Microbiology 39: 959–963.

Wong GA and Shear NH (2004) Is a drug alone sufficient to cause the drug hypersensitivity syndrome? Archives of Dermatology 140: 226–230.

Yamanishi K, Okuno T, Shiraki K et al. (1988) Identification of human herpesvirus‐6 as a causal agent for exanthem subitum. Lancet 1: 1065–1067.

Yoshikawa T, Ohashi M, Miyake F et al. (2009) Exanthem subitum‐associated encephalitis: nationwide survey in Japan. Pediatric Neurology 41: 353–358.

Zerr DM, Fann JR, Breiger D et al. (2011) HHV‐6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients. Blood 117: 5243–5249.

Zerr DM, Meier AS, Selke SS et al. (2005) A population‐based study of primary human herpesvirus 6 infection. New England Journal of Medicine 352: 768–776.

Further Reading

Black JB and Pellett PE (1999) Human herpesvirus 7. Reviews in Medical Virology 9: 245–262.

Braun DK, Dominguez G and Pellett PE (1997) Human herpesvirus 6. Clinical Microbiology Reviews 10: 521–567.

Ljungman P, de la Camara R, Cordonnier C et al. (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 Transplantation 42: 227–240.

Ljungman P and Singh N (2006) Human herpesvirus‐6 infection in solid organ and stem cell transplant recipients. Journal of Clinical Virology 37(suppl. 1): S87–S91.

Morissette G and Flamand L (2010) Herpesviruses and chromosomal integration. Journal of Virology 84: 12100–12109.

Roos KL (2008) CNS infections: progress in therapy, diagnosis, and prevention. Lancet Neurology 7: 18–19.

Tyler KL (2003) Human herpesvirus 6 and multiple sclerosis: the continuing conundrum. Journal of Infectious Diseases 187: 1360–1364.

Yoshikawa T (2003) Human herpesvirus‐6 and ‐7 infections in transplantation. Pediatric Transplantation 7: 11–17.

Zerr DM (2006) Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation. Journal of Clinical Virology 37(suppl. 1): S52–S56.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Ward, Katherine N(May 2013) Human Herpesviruses‐6 and ‐7 (HHV‐6A, HHV‐6B and HHV‐7). In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023616]