Human Herpesvirus Six
Encyclopedia
Human herpesvirus 6 is one of the eight known virus
es that are members of the human herpesvirus family. The Human herpesvirus 6 is a virus within the Betaherpesvirinae
subfamily of the genus, Roseolovirus
es. There are seven other types of viruses in this family. HHV-6 has two known variants: HHV-6A and HHV-6B. 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. While HHV-6A has not been linked to any diseases, HHV-6B 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.
(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.
, Syed Zaki Salahuddin, and Robert Gallo
first isolated and identified HHV-6 in 1986. Both variants of HHV-6 were discovered from people suffering from AIDS
and lymphoproliferative illnesses
. The isolation and cultivation of the virus was made possible from the widespread use of methods in the study of HIV
s (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”.
synthesis within 65 hours of infection.
on its host. One benefit from being host to the virus is that it works to suppress the replication of the HIV-1 when they coinfect the same cell. It is unknown as to why this occurs but there are some suggestions made through a study conducted by Carrigan et al. They suggest that the HHV-6 might work to inhibit its host cell’s macromolecular synthesis. This has significant implications for the treatment of patients with HIV and AIDS. However, even though HHV-6 can suppress the replication of HIV in the cells they coinfect and can itself destroy the host cell, there is not enough information to know if the virus can destroy enough cells in order to stop the progression of the disease.
(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.
Most primary infections are at an early age; primary infection in adults tend to be more severe.
, 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. 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.
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) only being observed in 10% of cases.
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. and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome
, fibromyalgia
, AIDS
, and temporal lobe epilepsy
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. There are no treatments specified in treating HHV-6, and most anti-herpes drugs have secondary effects on patients. There are clinical trials in using IFN to treat the virus but tends to work only before the virus is reactivated.
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es that are members of the human herpesvirus family. The Human herpesvirus 6 is a virus within the Betaherpesvirinae
Betaherpesvirinae
Betaherpesvirinae is a subfamily of Herpesviridae distinguished by reproducing less quickly than other subfamilies of Herpesviridae.Betaherpesvirinae establish latency in leukocytes...
subfamily of the genus, Roseolovirus
Roseolovirus
Roseolovirus refers to both Human herpesvirus 6 and Human herpesvirus 7, both members of the Betaherpesviridae subfamily of herpesvirus. They can both cause the childhood disease of roseola.-External links:* , New York Times* *...
es. There are seven other types of viruses in this family. HHV-6 has two known variants: HHV-6A and HHV-6B. 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. While HHV-6A has not been linked to any diseases, HHV-6B 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.
Groupings
HHV-6 is a member of the BetaherpesvirinaeBetaherpesvirinae
Betaherpesvirinae is a subfamily of Herpesviridae distinguished by reproducing less quickly than other subfamilies of Herpesviridae.Betaherpesvirinae establish latency in leukocytes...
(subfamily of the Herpesviridae) which also includes HHV-7 and Cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
(HHV-5 or HCMV). There are two subtypes of HHV-6 termed HHV-6A and HHV-6B.
History
Dharam AblashiDharam Ablashi
Dharam Ablashi is an American biomedical researcher born in India. He is best known for his co-discovery of Human herpesvirus 6 , an immunosuppressive and neurotropic virus that can cause encephalitis and seizures during a primary infection or when reactivated from latency in immunosuppressed...
, Syed Zaki Salahuddin, and Robert Gallo
Robert Gallo
Robert Charles Gallo is an American biomedical researcher. He is best known for his role in the discovery of the Human Immunodeficiency Virus , the infectious agent responsible for the Acquired Immune Deficiency Syndrome , and he has been a major contributor to subsequent HIV research.Gallo is the...
first isolated and identified HHV-6 in 1986. Both variants of HHV-6 were discovered from people suffering from AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
and lymphoproliferative illnesses
Lymphoproliferative disorders
Lymphoproliferative disorders refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in patients who have compromised immune systems...
. The isolation and cultivation of the virus was made possible from the widespread use of methods in the study of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
s (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”.
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.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.Effects on cells
Cells infected with HHV-6B experiences loss of DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
synthesis within 65 hours of infection.
Interactions
Human herpesvirus 6 lives primarily on humans and, while variants of the virus can cause mild to fatal illnesses, can live commensallyCommensalism
In ecology, commensalism is a class of relationship between two organisms where one organism benefits but the other is neutral...
on its host. One benefit from being host to the virus is that it works to suppress the replication of the HIV-1 when they coinfect the same cell. It is unknown as to why this occurs but there are some suggestions made through a study conducted by Carrigan et al. They suggest that the HHV-6 might work to inhibit its host cell’s macromolecular synthesis. This has significant implications for the treatment of patients with HIV and AIDS. However, even though HHV-6 can suppress the replication of HIV in the cells they coinfect and can itself destroy the host cell, there is not enough information to know if the virus can destroy enough cells in order to stop the progression of the disease.
Symptoms
The classical presentation of HHV-6 is as exanthema subitumExanthema subitum
Exanthema subitum , also referred to as roseola infantum , sixth disease and baby measles, or three-day fever, is a disease of children, generally under two years old, although it has been known to occur in eighteen year olds, whose manifestations...
(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.
Most primary infections are at an early age; primary infection in adults tend to be more severe.
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 and are associated with several more severe complications, such as encephalitisEncephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
, lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
, myocarditis
Myocarditis
Myocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...
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. 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.
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. Studies have found seroprevalence varying "from approximately 39 to 80% among ethnically diverse adult populations from Tanzania, Malaysia, Thailand, and Brazil". 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.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) only being observed in 10% of cases.
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.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. 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
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
-related disorders.
HHV-6 has been reported in multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
patients. and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
, fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, and temporal lobe epilepsy
Temporal lobe epilepsy
Temporal lobe epilepsy a.k.a. Psychomotor epilepsy, is a form of focal epilepsy, a chronic neurological condition characterized by recurrent seizures. Over 40 types of epilepsies are known. They fall into two main categories: partial-onset epilepsies and generalized-onset epilepsies...
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. There are no treatments specified in treating HHV-6, and most anti-herpes drugs have secondary effects on patients. There are clinical trials in using IFN to treat the virus but tends to work only before the virus is reactivated.