|Group:||Group I (dsDNA)|
Herpesviridae is a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein ("to creep"), referring to the latent, recurring infections typical of this group of viruses. Herpesviridae can cause latent or lytic infections.
At least five species of Herpesviridae – HSV-1 and HSV-2 (both of which can cause orolabial herpes and genital herpes), Varicella zoster virus (which causes chicken-pox and shingles), Epstein-Barr virus (which causes mononucleosis), and Cytomegalovirus – are extremely widespread among humans. More than 90% of adults have been infected with at least one of these, and a latent form of the virus remains in most people. In total, there are 8 herpesvirus types that infect humans: herpes simplex viruses 1 and 2, varicella-zoster virus, EBV (Epstein-Barr virus), human cytomegalovirus, human herpesvirus 6, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus. There are more than 130 herpesviruses, and some are from mammals, birds, fish, reptiles, amphibians, and molluscs.
Herpesviruses all share a common structure—all herpesviruses are composed of relatively large double-stranded, linear DNA genomes encoding 100-200 genes encased within an icosahedral protein cage called the capsid which is itself wrapped in a protein layer called the tegument containing both viral proteins and viral mRNAs and a lipid bilayer membrane called the envelope. This whole particle is known as a virion.
|Genus||Structure||Symmetry||Capsid||Genomic Arrangement||Genomic Segmentation|
Herpesvirus life cycle
Infection is initiated when a viral particle contacts a cell with specific types of receptor molecules on the cell surface. Following binding of viral envelope glycoproteins to cell membrane receptors, the virion is internalized and dismantled, allowing viral DNA to migrate to the cell nucleus. Within the nucleus, replication of viral DNA and transcription of viral genes occurs.
During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latency associated transcript (LAT) accumulate instead. In this fashion the virus can persist in the cell (and thus the host) indefinitely. While primary infection is often accompanied by a self-limited period of clinical illness, long-term latency is symptom-free.
Reactivation of latent viruses has been implicated in a number of diseases (e.g. Shingles, Pityriasis Rosea). Following activation, transcription of viral genes transitions from latency-associated LAT to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads to cell death. Clinically, lytic activation is often accompanied by emergence of non-specific symptoms such as low grade fever, headache, sore throat, malaise, and rash as well as clinical signs such as swollen or tender lymph nodes and immunological findings such as reduced levels of natural killer cells.
|Genus||Host Details||Tissue Tropism||Entry Details||Release Details||Replication Site||Assembly Site||Transmission|
|Iltovirus||Birds: galliform: psittacine||None||Cell receptor endocytosis||Budding||Nucleus||Nucleus||Oral-fecal; aerosol|
|Cytomegalovirus||Humans; monkeys||Epithelial mucosa||Glycoproteins||Budding||Nucleus||Nucleus||Urine; saliva|
|Mardivirus||Chickens; turkeys; quail||None||Cell receptor endocytosis||Budding||Nucleus||Nucleus||Aerosol|
|Rhadinovirus||Humans; mammals||B-lymphocytes||Glycoproteins||Budding||Nucleus||Nucleus||Sex; saliva|
|Roseolovirus||Humans||T-cells; B-cells; NK-cell; monocytes; macrophages; epithelial||Glycoproteins||Budding||Nucleus||Nucleus||Respiratory contact|
|Simplexvirus||Humans; mammals||Epithelial mucosa||Cell receptor endocytosis||Budding||Nucleus||Nucleus||Saliva|
|Scutavirus||Sea turtles||None||Cell receptor endocytosis||Budding||Nucleus||Nucleus||Aerosol|
The herpesvirus was first isolated from the blue wildebeest in 1960 by veterinary scientist Walter Plowright. The genus Herpesvirus was established in 1971 in the first report of the International Committee on Taxonomy of Viruses (ICTV). This genus consisted of 23 viruses and 4 groups of viruses. In the second ICTV report in 1976 this genus was elevated to family level - the Herpetoviridae. Because of possible confusion with viruses derived from reptiles this name was changed in the third report in 1979 to Herpesviridae. In this report the family Herpesviridae was divided into 3 subfamilies (Alphaherpesvirinae, Betaherpesvirinae and Gammaherpesvirinae) and 5 unnamed genera: 21 viruses were listed. In 2009 the family Herpesviridae was elevated to the order Herpesvirales. This elevation was necessitated by the discovery that the herpes viruses of fish and molluscs were only distantly related to those of birds and mammals. Two new families were created - the family Alloherpesviridae which incorporates bony fish and frog viruses and the family Malacoherpesviridae which contains those of molluscs.
This order currently has 3 families, 3 subfamilies plus 1 unassigned, 17 genera, 90 species and plus 48 as yet unassigned viruses.
Virus naming system
The system of naming herpes viruses was originated in 1973 and has been elaborated considerably since. The recommended naming system specified that each herpes virus should be named after the taxon (family or subfamily) to which its primary natural host belongs. The subfamily name is used for viruses from members of the family Bovidae or from primates (the virus name ending in –ine, e.g. bovine) and the host family name for other viruses (ending in –id, e.g. equid). Human herpes viruses have been treated as an exception (human rather than hominid). Following the host-derived term, the word herpes virus is added, followed by an Arabic numeral (1,2,3,...). These last two additions bear no implied meaning about taxonomic or biological properties of the virus.
Some exceptions to this system exist. A number of viruses' names (e.g. Epstein–Barr virus) are so widely used that it is impractical to attempt to insist on their replacement. This has led to a dual nomenclature in the literature for some herpes viruses. All herpes viruses described since this system was adopted have been named in accordance with it.
The three mammalian subfamilies - Alpha, Beta and Gamma - arose approximately  The major sublineages within these subfamilies were probably generated before the mammalian radiation of to . Speciations within sublineages took place in the last 80 million years probably with a major component of cospeciation with host lineages.to .
Immune system evasions
Herpesviruses are known for their ability to establish lifelong infections. One way this is possible is through immune evasion. Herpesviruses have found many different ways to evade the immune system. One such way is by encoding a protein mimicking human interleukin 10 (hIL-10) and another is by downregulation of the Major Histocompatibility Complex II (MHC II) in infected cells.
Research conducted on cytomegalovirus (CMV) indicates that the viral human IL-10 homolog, cmvIL-10, is important in inhibiting pro-inflammatory cytokine synthesis. The cmvIL-10 protein has 27% idesyntnjtity with hIL-10 and only one conserved residue out of the nine amino acids that make up the functional site for cytokine synthesis inhibition on hIL-10. There is, however, much similarity in the functions of hIL-10 and cmvIL-10. Both have been shown to down regulate IFN-γ, IL-1α, GM-CSF, IL-6 and TNF-α, which are all pro-inflammatory cytokines. They have also been shown to play a role in downregulating MHC I and MHC II and up regulating HLA-G (non-classical MHC I). These two events allow for immune evasion by suppressing the cell-mediated immune response and natural killer cell response, respectively. The similarities between hIL-10 and cmvIL-10 may be explained by the fact that hIL-10 and cmvIL-10 both use the same cell surface receptor, the hIL-10 receptor. One difference in the function of hIL-10 and cmvIL-10 is that hIL-10 causes human peripheral blood mononuclear cells (PBMC) to both increase and decrease in proliferation whereas cmvIL-10 only causes a decrease in proliferation of PBMCs. This indicates that cmvIL-10 may lack the stimulatory effects that hIL-10 has on these cells.
It was found that cmvIL-10 functions through phosphorylation of the Stat3 protein. It was originally thought that this phosphorylation was a result of the JAK-STAT pathway. However, despite evidence that JAK does indeed phosphorylate Stat3, its inhibition has no significant influence on cytokine synthesis inhibition. Another protein, PI3K, was also found to phosphorylate Stat3. PI3K inhibition, unlike JAK inhibition, did have a significant impact on cytokine synthesis. The difference between PI3K and JAK in Stat3 phosphorylation is that PI3K phosphorylates Stat3 on the S727 residue whereas JAK phosphorylates Stat3 on the Y705 residue. This difference in phosphorylation positions seems to be the key factor in Stat3 activation leading to inhibition of pro-inflammatory cytokine synthesis. In fact, when a PI3K inhibitor is added to cells, the cytokine synthesis levels are significantly restored. The fact that cytokine levels are not completely restored indicates there is another pathway activated by cmvIL-10 that is inhibiting cytokine system nthesis. The proposed mechanism is that cmvIL-10 activates PI3K which in turn activates PKB (Akt). PKB may then activate mTOR, which may target Stat3 for phosphorylation on the S727 residue.
Another one of the many ways in which herpes viruses evade the immune system is by down regulation of MHC I and MHC II. This is observed in almost every human herpesvirus. Down regulation of MHC I and MHC II can come about by many different mechanisms, most causing the MHC to be absent from the cell surface. As discussed above, one way is by a viral chemokine homolog such as IL-10. Another mechanism to down regulate MHCs is to encode viral proteins that detain the newly formed MHC in the endoplasmic reticulum (ER). The MHC cannot reach the cell surface and therefore cannot activate the T cell response. The MHCs can also be targeted for destruction in the proteasome or lysosome. The ER protein TAP also plays a role in MHC down regulation. Viral proteins inhibit TAP preventing the MHC from picking up a viral antigen peptide. This prevents proper folding of the MHC and therefore the MHC does not reach the cell surface.
Human herpesvirus types
|Human Herpesvirus (HHV) classification|
|Name||Synonym||Subfamily||Primary Target Cell||Pathophysiology||Site of Latency||Means of Spread|
|HHV‑1||Herpes simplex virus-1 (HSV-1)||α (Alpha)||Mucoepithelial||Oral and/or genital herpes (predominantly orofacial), as well as other herpes simplex infections||Neuron||Close contact (oral or sexually transmitted infection)|
|HHV-2||Herpes simplex virus-2 (HSV-2)||α||Mucoepithelial||Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infections||Neuron||Close contact (oral or sexually transmitted disease)|
|HHV-3||Varicella zoster virus (VZV)||α||Mucoepithelial||Chickenpox and shingles||Neuron||Respiratory and close contact (including sexually transmitted disease)|
|HHV-4||Epstein-Barr virus (EBV), lymphocryptovirus||γ (Gamma)||B cells and epithelial cells||Infectious mononucleosis, Burkitt's lymphoma, CNS lymphoma in AIDS patients,
post-transplant lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV-associated hairy leukoplakia
|B cell||Close contact, transfusions, tissue transplant, and congenital|
|HHV-5||Cytomegalovirus (CMV)||β (Beta)||Monocyte, lymphocyte, and epithelial cells||Infectious mononucleosis-like syndrome, retinitis||Monocyte, lymphocyte, and ?||Saliva, urine, breast milk|
|HHV-6A and 6B||Roseolovirus, Herpes lymphotropic virus||β||T cells and ?||Sixth disease (roseola infantum or exanthem subitum)||T cells and ?||Respiratory and close contact?|
|HHV-7||β||T cells and ?||(roseola infantum or exanthem subitum)||T cells and ?||?|
|HHV-8||Kaposi's sarcoma-associated herpesvirus
(KSHV), a type of rhadinovirus
|γ||Lymphocyte and other cells||Kaposi's sarcoma, primary effusion lymphoma, some types of multicentric Castleman's disease||B cell||Close contact (sexual), saliva?|
Herpesviruses of other animals
|Macaque monkey||CeHV-1||Cercopithecine herpesvirus-1, (Monkey B virus)||α||Very unusual, with only approximately 25 human cases reported. Untreated infection is often deadly; sixteen of the 25 cases resulted in fatal encephalomyelitis. At least four cases resulted in survival with severe neurologic impairment. Symptom awareness and early treatment are important for laboratory workers facing exposure.|
|Mouse||MuHV‑4||Murine gammaherpesvirus-68 (MHV-68)||γ||Zoonotic infection found in 4.5% of general population and more common in laboratory workers handling infected mice. ELISA tests show factor-of-four (x4) false positive results, due to antibody cross-reaction with other Herpes viruses.|
In animal virology, the most important herpesviruses belong to the subfamily Alphaherpesvirinae. Research on pseudorabies virus (PrV), the causative agent of Aujeszky's disease in pigs, has pioneered animal disease control with genetically modified vaccines. PrV is now extensively studied as a model for basic processes during lytic herpesvirus infection, and for unraveling molecular mechanisms of herpesvirus neurotropism, whereas bovine herpesvirus 1, the causative agent of bovine infectious rhinotracheitis and pustular vulvovaginitis, is analyzed to elucidate molecular mechanisms of latency. The avian infectious laryngotracheitis virus is phylogenetically distant from these two viruses and serves to underline similarity and diversity within the Alphaherpesvirinae.
- Subfamily Alphaherpesvirinae
- Genus Simplexvirus
- Genus Varicellovirus
- Bovine herpesvirus 1 causes infectious bovine rhinotracheitis, vaginitis, balanoposthitis, and abortion in cattle.
- Bovine herpesvirus 5 causes encephalitis in cattle.
- Caprine herpesvirus 1 causes conjunctivitis and respiratory disease in goats.
- Suid herpesvirus 1 causes Aujeszky's disease, also called pseudorabies.
- Equine herpesvirus 1 causes respiratory disease, neurological disease/paralysis, and spontaneous abortion in horses.
- Equine herpesvirus 3 causes coital exanthema in horses.
- Equine herpesvirus 4 causes rhinopneumonitis in horses.
- Canine herpesvirus 1 causes a severe hemorrhagic disease in puppies.
- Feline herpesvirus 1 causes feline viral rhinotracheitis and keratitis in cats.
- Duck herpesvirus 1 causes duck plague.
- Genus Mardivirus
- Genus Iltovirus
- Subfamily Betaherpesvirinae
- Subfamily Gammaherpesvirinae
- Genus Rhadinovirus
- Alcelaphine herpesvirus 1 causes bovine malignant catarrhal fever.
- Alcelaphine herpesvirus 2 causes an antelope and hartebeest version of MCF.
- Bovine herpesvirus 4
- Equine herpesvirus 2 causes equine cytomegalovirus infection.
- Equine herpesvirus 5
- Japanese macaque rhadinovirus
- Murid herpesvirus 4 Also known as Murine gammaherpesvirus-68 (MHV-68)
- Genus Rhadinovirus
Research is currently ongoing into a variety of side-effect or co-conditions related to the herpesviruses. These include:
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- In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. National Center for Infectious Diseases
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- John Carter, Venetia Saunders. Virology, Principles and Applications. John Wiley & Sons. ISBN 978-0-470-02386-0.
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- ICTV. "Virus Taxonomy: 2014 Release". Retrieved 15 June 2015.
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- Lin, Aifen; Huihui Xu; Weihua Yan (April 2007). "Modulation of HLA Expression in Human Cytomegalovirus Immune Evasion". Cellular and Molecular Immunology 4 (2): 91–98. PMID 17484802.
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- Whitley RJ (1996). Herpesviruses. in: Baron's Medical Microbiology (Baron S et al., eds.) (4th ed.). Univ of Texas Medical Branch. ISBN 0-9631172-1-1.
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- Weigler BJ (February 1992). "Biology of B virus in macaque and human hosts: a review". Clinical Infectious Diseases 14 (2): 555–67. doi:10.1093/clinids/14.2.555. PMID 1313312.
- Huff J, Barry P (2003). "B-Virus (Cercopithecine herpesvirus 1) Infection in Humans and Macaques: Potential for Zoonotic Disease". Emerg Infect Dis 9 (2): 246–50. doi:10.3201/eid0902.020272. PMC 2901951. PMID 12603998.
- Herpes-B Fact Sheet
- Hricova M, Mistrikova J (2007). "Murine gammaherpesvirus 68 serum antibodies in general human population". Acta virologica 51 (4): 283–7. PMID 18197737.
- Fenner, Frank J.; Gibbs, E. Paul J.; Murphy, Frederick A.; Rott, Rudolph; Studdert, Michael J.; White, David O. (1993). Veterinary Virology (2nd ed.). Academic Press, Inc. ISBN 0-12-253056-X.
- Estep, R. D.; Hansen, S. G.; Rogers, K. S.; Axthelm, M. K.; Wong, S. W. (2012). "Genomic Characterization of Japanese Macaque Rhadinovirus, a Novel Herpesvirus Isolated from a Nonhuman Primate with a Spontaneous Inflammatory Demyelinating Disease". Journal of Virology 87 (1): 512–523. doi:10.1128/JVI.02194-12. PMC 3536378. PMID 23097433.
|Wikispecies has information related to: Herpesviridae|
|Wikimedia Commons has media related to Herpesviridae.|
- ICTV International Committee on Taxonomy of Viruses (official site)
- Viralzone: Herpesviridae
- Animal viruses
- Article on Cercopithecine herpesvirus
- National B Virus Resource Center
- Pityriasis Rosea overview
- Herpes simplex: Host viral protein interactions.A database of Host/HSV-1 interactions
- Virus Pathogen Database and Analysis Resource (ViPR): Herpesviridae