Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection
- Cécile Tremblay, MD
Cécile Tremblay, MD
- Associate Professor
- University of Montreal, Canada
Human herpesvirus 6 (HHV-6) was first isolated and characterized from patients with lymphoproliferative disorders  and was originally named human B-lymphotropic virus. Its name was changed to human herpesvirus 6 as its tropism was further characterized .
The virology, pathogenesis, and epidemiology of HHV-6 infection will be discussed here. The clinical manifestations, diagnosis, and treatment in adults and children are presented separately; HHV-6 infection in hematopoietic cell transplant recipients is also discussed elsewhere. (See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults" and "Human herpesvirus 6 infection in children: Clinical manifestations; diagnosis; and treatment" and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)
HHV-6 is a member of the Herpesviridae family. Its genetic and biologic similarities to human cytomegalovirus (CMV) have prompted its classification in the beta herpesvirus subfamily (genus Roseolovirus, along with human herpesvirus 7 [HHV-7]) . There are two HHV-6 variants, HHV-6A and HHV-6B. Based on their distinctive biological properties and genome sequences, HHV-6A and HHV-6B are classified as two distinct herpesvirus species . HHV-6A and HHV-6B also differ in epidemiology, growth properties, antigenic properties, and restriction endonuclease profiles [5-8]. The nucleotide sequence identity between the two variants ranges from 75 to 95 percent depending upon which gene is compared.
VIROLOGY AND PATHOGENESIS
As with other herpes viruses, mature HHV-6 virions are double-stranded DNA viruses, approximately 200 nm in diameter and are composed of four main structural elements: an electron-dense core, a capsid with icosahedral symmetry, a tegument, and an outer envelope.
Cell tropism — HHV-6 replicates most efficiently in vitro in activated primary T cells as well as in continuous T cell lines. However, the virus can also replicate with varying efficiency in a wide array of host cell types including monocytes/macrophages, natural killer cells, astrocytes, megakaryocytes, and glial cell lineages [2,9-12]. HHV-6 can also be recovered in vivo from a broad range of tissues such as lymph nodes, peripheral blood mononuclear cells (PBMCs), renal tubular cells, salivary glands, and the central nervous system [13-19]. HHV-6 has also been identified in astrocytes from gliomas, suggesting a potential role in tumorigenesis [20,21].
- Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234:596.
- Ablashi DV, Salahuddin SZ, Josephs SF, et al. HBLV (or HHV-6) in human cell lines. Nature 1987; 329:207.
- Yamanishi K, Mori Y, Pellett PE. Human herpesvirus 6 and 7. In: Fields Virology, 6th edition, Knipe DM, Howley P. (Eds), Wolters Kluwer Health, Philadelphia 2013. Vol 2, p.2058.
- International Committee on Taxonomy of Viruses. ICTV Master Species List 2011. http://talk.ictvonline.org/files/ictv_documents/m/msl/4090.aspx (Accessed on June 27, 2012).
- Ablashi DV, Balachandran N, Josephs SF, et al. Genomic polymorphism, growth properties, and immunologic variations in human herpesvirus-6 isolates. Virology 1991; 184:545.
- Aubin JT, Agut H, Collandre H, et al. Antigenic and genetic differentiation of the two putative types of human herpes virus 6. J Virol Methods 1993; 41:223.
- Dewhurst S, Chandran B, McIntyre K, et al. Phenotypic and genetic polymorphisms among human herpesvirus-6 isolates from North American infants. Virology 1992; 190:490.
- Achour A, Malet I, Le Gal F, et al. Variability of gB and gH genes of human herpesvirus-6 among clinical specimens. J Med Virol 2008; 80:1211.
- Cermelli C, Concari M, Carubbi F, et al. Growth of human herpesvirus 6 in HEPG2 cells. Virus Res 1996; 45:75.
- Chen M, Popescu N, Woodworth C, et al. Human herpesvirus 6 infects cervical epithelial cells and transactivates human papillomavirus gene expression. J Virol 1994; 68:1173.
- He J, McCarthy M, Zhou Y, et al. Infection of primary human fetal astrocytes by human herpesvirus 6. J Virol 1996; 70:1296.
- Luka J, Okano M, Thiele G. Isolation of human herpesvirus-6 from clinical specimens using human fibroblast cultures. J Clin Lab Anal 1990; 4:483.
- Levine PH, Jahan N, Murari P, et al. Detection of human herpesvirus 6 in tissues involved by sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). J Infect Dis 1992; 166:291.
- Cone RW, Huang ML, Ashley R, Corey L. Human herpesvirus 6 DNA in peripheral blood cells and saliva from immunocompetent individuals. J Clin Microbiol 1993; 31:1262.
- Kondo K, Kondo T, Okuno T, et al. Latent human herpesvirus 6 infection of human monocytes/macrophages. J Gen Virol 1991; 72 ( Pt 6):1401.
- Okuno T, Higashi K, Shiraki K, et al. Human herpesvirus 6 infection in renal transplantation. Transplantation 1990; 49:519.
- Krueger GR, Wassermann K, De Clerck LS, et al. Latent herpesvirus-6 in salivary and bronchial glands. Lancet 1990; 336:1255.
- Challoner PB, Smith KT, Parker JD, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A 1995; 92:7440.
- Luppi M, Barozzi P, Maiorana A, et al. Human herpesvirus 6 infection in normal human brain tissue. J Infect Dis 1994; 169:943.
- Crawford JR, Santi MR, Thorarinsdottir HK, et al. Detection of human herpesvirus-6 variants in pediatric brain tumors: association of viral antigen in low grade gliomas. J Clin Virol 2009; 46:37.
- Crawford JR, Santi MR, Cornelison R, et al. Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors. J Neurooncol 2009; 95:49.
- Kondo K, Kondo T, Shimada K, et al. Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection. J Med Virol 2002; 67:364.
- Andre-Garnier E, Milpied N, Boutolleau D, et al. Reactivation of human herpesvirus 6 during ex vivo expansion of circulating CD34+ haematopoietic stem cells. J Gen Virol 2004; 85:3333.
- Santoro F, Kennedy PE, Locatelli G, et al. CD46 is a cellular receptor for human herpesvirus 6. Cell 1999; 99:817.
- Mori Y, Yang X, Akkapaiboon P, et al. Human herpesvirus 6 variant A glycoprotein H-glycoprotein L-glycoprotein Q complex associates with human CD46. J Virol 2003; 77:4992.
- Smith A, Santoro F, Di Lullo G, et al. Selective suppression of IL-12 production by human herpesvirus 6. Blood 2003; 102:2877.
- Karp CL, Wysocka M, Wahl LM, et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science 1996; 273:228.
- Tang H, Serada S, Kawabata A, et al. CD134 is a cellular receptor specific for human herpesvirus-6B entry. Proc Natl Acad Sci U S A 2013; 110:9096.
- Nacheva EP, Ward KN, Brazma D, et al. Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal sites. J Med Virol 2008; 80:1952.
- Mori Y, Koike M, Moriishi E, et al. Human herpesvirus-6 induces MVB formation, and virus egress occurs by an exosomal release pathway. Traffic 2008; 9:1728.
- Lusso P, Gallo RC, DeRocco SE, Markham PD. CD4 is not the membrane receptor for HHV-6. Lancet 1989; 1:730.
- Di Luca D, Katsafanas G, Schirmer EC, et al. The replication of viral and cellular DNA in human herpesvirus 6-infected cells. Virology 1990; 175:199.
- Lusso P, Malnati M, De Maria A, et al. 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.
- Singh N. Interactions between viruses in transplant recipients. Clin Infect Dis 2005; 40:430.
- Gupta S, Agrawal S, Gollapudi S. Differential effect of human herpesvirus 6A on cell division and apoptosis among naive and central and effector memory CD4+ and CD8+ T-cell subsets. J Virol 2009; 83:5442.
- Takemoto M, Imasawa T, Yamanishi K, Mori Y. Role of dendritic cells infected with human herpesvirus 6 in virus transmission to CD4(+) T cells. Virology 2009; 385:294.
- Tai AK, Luka J, Ablashi D, Huber BT. HHV-6A infection induces expression of HERV-K18-encoded superantigen. J Clin Virol 2009; 46:47.
- Flamand L, Stefanescu I, Menezes J. Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15. J Clin Invest 1996; 97:1373.
- Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 1994; 331:432.
- Gompels UA, Nicholas J, Lawrence G, et al. The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 1995; 209:29.
- Lindquester GJ, Inoue N, Allen RD, et al. Restriction endonuclease mapping and molecular cloning of the human herpesvirus 6 variant B strain Z29 genome. Arch Virol 1996; 141:367.
- Pfeiffer B, Berneman ZN, Neipel F, et al. Identification and mapping of the gene encoding the glycoprotein complex gp82-gp105 of human herpesvirus 6 and mapping of the neutralizing epitope recognized by monoclonal antibodies. J Virol 1993; 67:4611.
- Isegawa Y, Ping Z, Nakano K, et al. Human herpesvirus 6 open reading frame U12 encodes a functional beta-chemokine receptor. J Virol 1998; 72:6104.
- Milne RS, Mattick C, Nicholson L, et al. RANTES binding and down-regulation by a novel human herpesvirus-6 beta chemokine receptor. J Immunol 2000; 164:2396.
- Horvat RT, Wood C, Balachandran N. Transactivation of human immunodeficiency virus promoter by human herpesvirus 6. J Virol 1989; 63:970.
- Lusso P, Ensoli B, Markham PD, et al. Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature 1989; 337:370.
- Lusso P, Malnati MS, Garzino-Demo A, et al. Infection of natural killer cells by human herpesvirus 6. Nature 1993; 362:458.
- Ranger S, Patillaud S, Denis F, et al. Seroepidemiology of human herpesvirus-6 in pregnant women from different parts of the world. J Med Virol 1991; 34:194.
- Levy JA, Ferro F, Greenspan D, Lennette ET. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. Lancet 1990; 335:1047.
- Okuno T, Takahashi K, Balachandra K, et al. Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol 1989; 27:651.
- Brown NA, Sumaya CV, Liu CR, et al. Fall in human herpesvirus 6 seropositivity with age. Lancet 1988; 2:396.
- Zerr DM, Meier AS, Selke SS, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med 2005; 352:768.
- Dewhurst S, McIntyre K, Schnabel K, Hall CB. Human herpesvirus 6 (HHV-6) variant B accounts for the majority of symptomatic primary HHV-6 infections in a population of U.S. infants. J Clin Microbiol 1993; 31:416.
- Kasolo FC, Mpabalwani E, Gompels UA. Infection with AIDS-related herpesviruses in human immunodeficiency virus-negative infants and endemic childhood Kaposi's sarcoma in Africa. J Gen Virol 1997; 78 ( Pt 4):847.
- Knox KK, Carrigan DR. Active HHV-6 infection in the lymph nodes of HIV-infected patients: in vitro evidence that HHV-6 can break HIV latency. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11:370.
- Hall CB, Caserta MT, Schnabel KC, et al. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis 1998; 26:132.
- De Bolle L, Van Loon J, De Clercq E, Naesens L. Quantitative analysis of human herpesvirus 6 cell tropism. J Med Virol 2005; 75:76.
- American Academy of Pediatrics. Human herpesvirus 6 (including roseola) and 7. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.449.
- Hall CB, Caserta MT. Exanthem subitum (Roseola infantum). Herpes 1999; 6:64.
- Wyatt LS, Frenkel N. Human herpesvirus 7 is a constitutive inhabitant of adult human saliva. J Virol 1992; 66:3206.
- Di Luca D, Mirandola P, Ravaioli T, et al. Human herpesviruses 6 and 7 in salivary glands and shedding in saliva of healthy and human immunodeficiency virus positive individuals. J Med Virol 1995; 45:462.
- Pereira CM, Gasparetto PF, Corrêa ME, et al. Human herpesvirus 6 in oral fluids from healthy individuals. Arch Oral Biol 2004; 49:1043.
- Roush KS, Domiati-Saad RK, Margraf LR, et al. Prevalence and cellular reservoir of latent human herpesvirus 6 in tonsillar lymphoid tissue. Am J Clin Pathol 2001; 116:648.
- Baillargeon J, Piper J, Leach CT. Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and nonpregnant women. J Clin Virol 2000; 16:149.
- Dahl H, Fjaertoft G, Norsted T, et al. Reactivation of human herpesvirus 6 during pregnancy. J Infect Dis 1999; 180:2035.
- Hall CB, Caserta MT, Schnabel KC, et al. Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). J Pediatr 2004; 145:472.
- Aubin JT, Poirel L, Agut H, et al. Intrauterine transmission of human herpesvirus 6. Lancet 1992; 340:482.
- Ashshi AM, Cooper RJ, Klapper PE, et al. Detection of human herpes virus 6 DNA in fetal hydrops. Lancet 2000; 355:1519.
- Asano Y, Yoshikawa T, Suga S, et al. Fatal fulminant hepatitis in an infant with human herpesvirus-6 infection. Lancet 1990; 335:862.