Human herpesvirus 6

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Human herpesvirus 6
Electron micrograph of HHV-6
Virus classification
Group: Group I (dsDNA)
Family: Herpesviridae
Subfamily: Betaherpesvirinae
Genus: Roseolovirus
Species

Human herpesvirus 6 (HHV-6)

Human herpesvirus 6 (HHV-6) is one of the eight known viruses that are members of the human herpesvirus family. The Human herpesvirus 6 is a virus within the Betaherpesvirinae subfamily of the genus, Roseoloviruses. There are seven other types of viruses in this family. HHV-6 has two known variants: HHV-6A and HHV-6B.[1] Although the two variants are highly distinctive, diagnostic tests are usually unable to distinguish the specific culprit of an infection. The virus makes its home in almost 100% of the human population all over the world.[2] HHV-6A is more frequently found in patients with neuroinflammatory diseases such as multiple sclerosis,[3] while HHV-6B primary infection is the cause of the common childhood illness, exanthem subitum (also known as roseola infantum or sixth disease), a near-universal childhood disease and other febrile illnesses. Additionally, HHV-6B reactivation is commmon in transplant recipients, which can cause several clinical manifestations such as encephalitis, bone marrow suprression and pneumonitis.[4]

Contents

[edit] Groupings

HHV-6 is a member of the Betaherpesvirinae (subfamily of the Herpesviridae) which also includes HHV-7 and Cytomegalovirus (HHV-5 or HCMV). There are two subtypes of HHV-6 termed HHV-6A and HHV-6B.[5]

[edit] History

Dharam Ablashi, Syed Zaki Salahuddin, and Robert Gallo first isolated and identified HHV-6 in 1986.[6] Both variants of HHV-6 were discovered from people suffering from AIDS and lymphoproliferative illnesses and was originally named human B-lymphotropic virus (HBLV).[1] The isolation and cultivation of the virus was made possible from the widespread use of methods in the study of HIVs (human immunodeficiency viruses). With the isolation methods, scientists discovered that the virus appeared to have two different strains. After many studies, the virus was subdivided into two distinct variants that differed in “epidemiology, growth properties, reactivity with monoclonal antibodies (MAb), restriction endonuclease profiles, and nucleotide sequences”.[1]

[edit] Biology

[edit] Structure

Like all other herpesviruses, HHV-6 has four elements to its structure: an electron-dense core, a protein shell (capsid), a protective layer (tegument), and an outer layer in which “virally encoded glycoproteins” (any of a class of proteins that have carbohydrate groups attached to the polypeptide chain) and proteins from the membrane are set. The process of HHV-6 maturation starts at the nucleus, where the assembly of nucleocapsids takes place. After the capsids are made, they stay in the nucleus to attain teguments. Once the capsids acquire the teguments, they are released into the cytoplasm through the blending of the nuclear membrane and the tegusome, a “spherical compartment” with a membrane layer.[1]

[edit] Genome

The structure of the HHV-6 genome is a linear, double-stranded molecule. The virus contains repetitions of the hexanucleotide at the ends, although the HHV-6A contains more repeated sequences than HHV-6B. Like other herpesviruses, HHV-6 contains little non-coding DNA and also shares similar amino acids and gene organization.[1] The nucleotide sequence identity between the two strains is 90%.[7]

[edit] Effects on cells

Cells infected with HHV-6B experiences loss of DNA synthesis within 65 hours of infection.

[edit] Interactions

Human herpesvirus 6 lives primarily on humans and, while variants of the virus can cause mild to fatal illnesses, can live commensally on its host.[1] It has been demonstrated that HHV-6 fosters the progression of HIV-1 upon coinfection in T cells.[8] HHV-6 upregulates the expression of the primary HIV receptor CD4, thus expanding the range of HIV susceptible cells. Several studies also have shown that HHV-6 infection increases production of inflammatory cytokines that enhance in vitro expression of HIV-1, such as TNF-alpha,[9] IL-1 beta , and IL-8.[10] A more recent in vivo study shows HHV-6A coinfection to dramatically accelerate the progression from HIV to full blown AIDS in pigtailed macaques.[11]

[edit] Symptoms

The classical presentation of primary HHV-6 infection is as exanthema subitum (ES) or "roseola", featuring a high temperature followed by a rash. However recent studies show that a rash is not a distinguishing feature of HHV-6 infections, with rates similar to non-HHV-6 infections - 10-20% of febrile children in both groups, in one US study. This study recording HHV6 infection in children attending hospital with fever found that 15% had HHV-6. HHV-6 infections more frequently presented with high temperatures (over 40C), at a rate of around two thirds compare to less than half in the non-HHV-6 patients. Similarly significant differences were seen in malaise and irritability, and in tympanic membrane inflammation.[1]

Most primary infections are at an early age; primary infection in adults tend to be more severe.[1]

[edit] Epidemiology

[edit] Age

Humans acquire the virus at an early age, some as early as less than one month of age. HHV-6 primary infections account for up to 20% of infant emergency room visits for fever in the United States[12] and are associated with several more severe complications, such as encephalitis, lymphadenopathy, myocarditis and myelosuppression. The prevalence of the virus in the body increases with age (rates of infection are highest among infant between 6 and 12 months old) and it is hypothesized that this is due to the loss of maternal antibodies in a child that protect him or her from infections[1]. There are inconsistencies with the correlations between age and seropositivity; according to reports, there is a decrease of seropositivity with the increase of age, some see no significant decline, and others report that there is sometimes an increased rate of seropositivity after the age of 62. After primary infection, latency is established in myeloid and bone marrow progenitors and exists for the lifetime of the host.

[edit] Geographical Distribution

The virus is known to be widespread around the world. Rates of HHV6 infection of 64 - 83% by age 13 months have been reported for countries including the United States, United Kingdom, Japan and Taiwan.[1] Studies have found seroprevalence varying "from approximately 39 to 80% among ethnically diverse adult populations from Tanzania, Malaysia, Thailand, and Brazil".[1] There are no significant differences among ethnic groups living in the same geographical location or between sexes. While HHV-6B is present in almost 100% of the world’s population, HHV-6A appears to be less frequent in Japan, North America, and Europe[1].

HHV-6B is responsible for up to 93% of primary infections in Europe and North America. Such infections usually cause fever, with exanthem subitum (roseola infantum)[13] only being observed in 10% of cases.

[edit] Transmission

The transmission of the virus is not well known, but the most common way is through the saliva. Both HHV-6B and HHV-7 are found on human saliva, the former being at a lower frequency. Studies report varying rates of prevalence of HHV-6 in saliva (between 3% - 90%), which might point to the salivary glands as a container for persistent or latent viral infections.[1]

[edit] Clinical Significance

Diagnosis for the virus, particularly HHV-6B, is vital for the patient because of the infection’s adverse effects. Symptoms that point to this infection, such as rashes, go unnoticed in patients that receive antibiotics because they can be misinterpreted as a side-effect of the medicine.[1] As a result, the patient is taken off the medication and the infection continues to grow, leading to potentially severe consequences. HHV-6B is known to be associated with the childhood disease roseola infantum, as well as other illnesses caused by the infection. These include hepatitis, febrile convulsions, and encephalitis. Children who suffer from ES, caused by an HHV-6B infection, experience fevers lasting 3 to 5 days; rashes on the torso, neck, and face; and sometimes febrile convulsions, however, the symptoms are not always present together. Primary infections in adults are rare since most occurrences are in children. When the infection does occur for the first time in an adult, the symptoms can be severe.

The virus periodically re-activates from this latent state, with HHV-6 DNA being detectable in 20-25% of healthy adults in the United States. In the immunocompetent setting, these re-activations are often asymptomatic, but in immunosuppressed individuals there can be serious complications. HHV-6 re-activation causes severe disease in transplant recipients and can lead to graft rejection, often in consort with other betaherpesviridae. Likewise in HIV/AIDS, HHV-6 re-activations cause disseminated infections leading to end organ disease and death. Although up to 100% of the population are exposed (seropositive) to HHV-6, most by 3 years of age, there are rare cases of primary infections in adults. In the United States, these have been linked more with HHV-6A, which is thought to be more pathogenic and more neurotropic and has been linked to several central nervous system-related disorders.

HHV-6 has been reported in multiple sclerosis patients.[14] and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome,[15] fibromyalgia, AIDS,[16] and temporal lobe epilepsy[17] but no definitive link has been established.

Finding a treatment is difficult when HHV-6 virus reactivation occurs after a transplant surgery because the patient takes immunosuppressants in order for the body to accept the transplant. However, the suppressants aid in the activation and culture of the virus.[18] There are no treatments specified in treating HHV-6, and most anti-herpes drugs have secondary effects on patients.[19] There are clinical trials in using IFN to treat the virus but tends to work only before the virus is reactivated.

[edit] References

  1. ^ a b c d e f g h i j k l m n Braun, Daniel K., et al. Human Herpesvirus 6 Clinical Microbiology Reviews 10 (1997): 521-549. http://cmr.asm.org/cgi/reprint/10/3/521
  2. ^ Jaworska J, Gravel A, Flamand L. Divergent susceptibilities of human herpesvirus 6 variants to type I interferons PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 (2010): 8369-8374.
  3. ^ Alvarez-Lafuente R, García-Montojo M, De las Heras V, Bartolomé M, Arroyo R. Clinical parameters and HHV-6 active replication in relapsing-remitting multiple sclerosis patients. J Clin Virol. 2006 Dec;37 Suppl 1:S24-6.
  4. ^ Yoshikawa, T. 2004. Human herpesvirus 6 infection in hematopoietic stem cell transplant patients. Br J Haematol 124:421-32.
  5. ^ "Other Herpesviruses: HHV-6, HHV-7, HHV-8, HSV-1 and -2, VZV.". American Journal of Transplantation (Blackwell Munksgaard) 4 Suppl 10: 66. 2004. doi:10.1111/j.1600-6135.2004.00697.x. PMID 15504215. ;Widen, B. F.; Lowings, J. P.; Belak, S.; Banks, M. (August 1999). "Development of a PCR system for porcine cytomegalovirus detection and determination of the putative partial sequence of its DNA polymerase gene.". Epidemiology and Infection (Cambridge University Press) 123 (1): 177–180. doi:10.1017/S0950268899002599. PMC 2810741. PMID 10487654. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2810741. 
  6. ^ Anderson L (September 1988). "Human retrovirus family: cancer, central nervous system disease, and AIDS". J. Natl. Cancer Inst. 80 (13): 987–9. doi:10.1093/jnci/80.13.987. PMID 2842514. http://jnci.oxfordjournals.org/cgi/pdf_extract/80/13/987. 
  7. ^ Dominguez, G., T. R. Dambaugh, F. R. Stamey, S. Dewhurst, N. Inoue, and P. E. Pellett. 1999. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol 73:8040-52.
  8. ^ Lusso P, De Maria A, Malnati M, Lori F, DeRocco SE, Baseler M, Gallo RC. Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature. 1991 Feb 7;349(6309):533-5.
  9. ^ Arena A, Liberto MC, Capozza AB, Focà A. Productive HHV-6 infection in differentiated U937 cells: role of TNF alpha in regulation of HHV-6. New Microbiol. 1997 Jan;20(1):13-20.
  10. ^ Inagi R, Guntapong R, Nakao M, Ishino Y, Kawanishi K, Isegawa Y, Yamanishi K. Human herpesvirus 6 induces IL-8 gene expression in human hepatoma cell line, Hep G2. J Med Virol. 1996 May;49(1):34-40.
  11. ^ Lusso P, Crowley RW, Malnati MS, Di Serio C, Ponzoni M, Biancotto A, Markham PD, Gallo RC. Human herpesvirus 6A accelerates AIDS progression in macaques. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5067-72.
  12. ^ [1] Human Herpesvirus-6 Infection in Children - A Prospective Study of Complications and Reactivation, Hall et al... N Engl J Med. 1994 Aug 18;331(7):432-8
  13. ^ Newly Found Herpes Virus Is Called Major Cause of Illness in Young, New York Times
  14. ^ Alvarez-Lafuente R, Martín-Estefanía C, de las Heras V, et al. (February 2002). "Prevalence of herpesvirus DNA in MS patients and healthy blood donors". Acta Neurol. Scand. 105 (2): 95–9. doi:10.1034/j.1600-0404.2002.1o050.x. PMID 11903118. 
  15. ^ Komaroff AL. (December 2006). "Is human herpesvirus-6 a trigger for chronic fatigue syndrome". J Clin Virol. 37 (Suppl 1): S39–46. doi:10.1016/S1386-6532(06)70010-5. PMID 17276367. http://www.hhv-6foundation.org/hhv6cfs_komaroff.html. 
  16. ^ HHV-6 and AIDS, Wisconsin Viral Research Group
  17. ^ Fotheringham J, Donati D, Akhyani N, Fogdell-Hahn A, Vortmeyer A, Heiss JD, Williams E, Weinstein S, Bruce DA, Gaillard WD, Sato S, Theodore WH, Jacobson S (2007). "Association of human herpesvirus-6B with mesial temporal lobe epilepsy". PLoS Med. 4 (5): e180. doi:10.1371/journal.pmed.0040180. PMC 1880851. PMID 17535102. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1880851. 
  18. ^ Shiley K, Blumberg E. Herpes Viruses in Transplant Recipients: HSV, VZV, Human Herpes Viruses, and EBV Hematology-Oncology Clinics of North America 25 (2011) : 176 – 177
  19. ^ Jaworska J, Gravel A, Flamand L. Divergent susceptibilities of human herpesvirus 6 variants to type I interferon PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 (2010): 8369-8374.
Other
Ungrouped

M: INT, SF, LCT

noco(i/b/d/q/u/r/p/m/k/v/f)/cong/tumr(n/e/d), sysi/epon

proc, drug (D2/3/4/5/8/11)
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