| Herpesviridae | |
|---|---|
 | |
Virus classification | |
| (unranked): | Virus |
| Realm: | Duplodnaviria |
| Kingdom: | Heunggongvirae |
| Phylum: | Peploviricota |
| Class: | Herviviricetes |
| Order: | Herpesvirales |
| Family: | Orthoherpesviridae |
| Subfamilies and genera | |
See text | |
Orthoherpesviridae, previously named and more widely known asHerpesviridae, is a largefamily ofDNA viruses that cause infections and certain diseases in animals, including humans.[1][2][3] The members of this family are commonly known asherpesviruses. The family name is derived from the Greek wordἕρπειν (herpein 'to creep'), referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles).[4] In 1971, theInternational Committee on the Taxonomy of Viruses (ICTV) establishedHerpesvirus as a genus with 23 viruses among four groups.[5] Since then, the number of identified herpesviruses has grown to more than 100.[6] Herpesviruses can cause bothlatent andlytic infections.
Nine herpesvirus types are known to primarily infect humans,[7] at least five of which are extremely widespread among most human populations, and which cause common diseases:herpes simplex 1 and 2 (HSV-1 and HSV-2, also known as HHV-1 and HHV-2; both of which can causeorolabial andgenital herpes),varicella zoster (VZV or HHV-3; the cause ofchickenpox andshingles),Epstein–Barr (EBV or HHV-4; implicated in several diseases, includingmononucleosis and some cancers), andhuman cytomegalovirus (HCMV or HHV-5). More than 90% of adults have been infected with at least one of these, and alatent form of the virus remains in almost all humans who have been infected.[8][9][10] Other human herpesviruses arehuman herpesvirus 6A and 6B (HHV-6A and HHV-6B) andhuman herpesvirus 7 (HHV-7), which are the etiological agents forRoseola, and HHV-8 (also known as KSHV) which is responsible for causingKaposi's sarcoma.[7] HHV here stands for "Human Herpesvirus".
In total, more than 130 herpesviruses are known,[11] some of them from mammals, birds, fish, reptiles, amphibians, and molluscs.[7] Among the animal herpesviruses arepseudorabies virus causingAujeszky's disease in pigs, andbovine herpesvirus 1 causingbovine infectious rhinotracheitis andpustular vulvovaginitis.
The family has the following subfamilies and genera:[6]
A number of other herpesviruses were previously recognized as species but were abolished, so their exact taxonomic placement is uncertain. These viruses include:Chelonid alphaherpesvirus 6,Cercopithecine gammaherpesvirus 14,Equid gammaherpesvirus 7,Iguanid herpesvirus 2,Phocid gammaherpesvirus 2, andSaguinine gammaherpesvirus 1.[12]
All members of theHerpesviridae share a common structure; a relatively large, monopartite, double-stranded, linearDNAgenome encoding 100–200genes encased within anicosahedral protein cage (with T=16 symmetry) called thecapsid, which is itself wrapped in a protein layer called thetegument containing both viral proteins and viral mRNAs and alipid bilayer membrane called theenvelope. This whole particle is known as avirion.The structural components of a typical HSV virion are the Lipid bilayer envelope, Tegument, DNA, Glycoprotein spikes and Nucleocapsid. The four-component Herpes simplex virion encompasses the double-stranded DNA genome into an icosahedral nucleocapsid. There is tegument around. Tegument contains filaments, each 7 nm wide. It is an amorphous layer with some structured regions. Finally, it is covered with a lipoprotein envelope. There are spikes made of glycoprotein protruding from each virion. These can expand the diameter of the virus to 225 nm. The diameters of virions without spikes are around 186 nm. There are at least two unglycosylated membrane proteins in the outer envelope of the virion. There are also 11 glycoproteins. These are gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL and gM. Tegument contains 26 proteins. They have duties such as capsid transport to the nucleus and other organelles, activation of early gene transcription, and mRNA degradation. The icosahedral nucleocapsid is similar to that of tailed bacteriophage in the orderCaudovirales. This capsid has 161 capsomers consisting of 150 hexons and 11 pentons, as well as a portal complex that allows entry and exit of DNA into the capsid.[13][14]
All herpesviruses are nuclear-replicating—the viralDNA istranscribed tomRNA within the infected cell'snucleus.[citation needed]
Infection is initiated when a viral particle contacts a cell with specific types ofreceptor molecules on the cell surface. Following binding of viral envelopeglycoproteins 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 andtranscription of viral genes occurs.[citation needed]
During symptomatic infection, infected cells transcribelytic viral genes. In some host cells, a small number of viral genes termedlatency-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.[citation needed]
Chromatin dynamics regulate the transcription competency of entire herpes virus genomes. When the virus enters a cell, the cellular immune response is to protect the cell. The cell does so by wrapping the viral DNA around histones and condensing it into chromatin, causing the virus to become dormant, or latent. If cells are unsuccessful and the chromatin is loosely bundled, the viral DNA is still accessible. The viral particles can turn on their genes and replicate using cellular machinery to reactivate, starting a lytic infection.[15]
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 LAT to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads tocell death. Clinically, lytic activation is often accompanied by emergence ofnonspecific symptoms, such as low-grade fever, headache, sore throat,malaise, and rash, as well as clinical signs such as swollen or tenderlymph nodes and immunological findings such as reduced levels ofnatural killer cells.[citation needed]
In animal models, local trauma and system stress have been found to induce reactivation of latent herpesvirus infection. Cellular stressors like transient interruption of protein synthesis and hypoxia are also sufficient to induce viral reactivation.[16]
| Genus | Subfamily | Host details | Tissue tropism | Entry details | Release details | Replication site | Assembly site | Transmission |
|---|---|---|---|---|---|---|---|---|
| Iltovirus | α | Birds: galliform: psittacine | None | Cell receptor endocytosis | Budding | Nucleus | Nucleus | Oral-fecal, aerosol |
| Proboscivirus | β | Elephants | None | Glycoproteins | Budding | Nucleus | Nucleus | Contact |
| Cytomegalovirus | β | Humans; monkeys | Epithelial mucosa, hematopoietic (blood) lineage cells | Glycoproteins | Budding | Nucleus | Nucleus | Urine, saliva |
| Mardivirus | α | Chickens; turkeys; quail | None | Cell receptor endocytosis | Budding | Nucleus | Nucleus | Aerosol |
| Rhadinovirus | γ | Humans; mammals | B-lymphocytes | Glycoproteins | Budding | Nucleus | Nucleus | Sex, saliva |
| Macavirus | γ | Mammals | B-lymphocytes | Glycoproteins | Budding | Nucleus | Nucleus | Sex, saliva |
| Roseolovirus | β | Humans | T-cells; B-cells; NK-cell; monocytes; macrophages; epithelial | Glycoproteins | Budding | Nucleus | Nucleus | Respiratory contact |
| Simplexvirus | α | Humans; mammals | Epithelial mucosa | Cell receptor endocytosis | Budding | Nucleus | Nucleus | Sex, saliva |
| Scutavirus | α | Sea turtles | None | Cell receptor endocytosis | Budding | Nucleus | Nucleus | Aerosol |
| Varicellovirus | α | Mammals | Epithelial mucosa | Glycoproteins | Budding | Nucleus | Nucleus | Aerosol |
| Percavirus | γ | Mammals | B-lymphocytes | Glycoproteins | Budding | Nucleus | Nucleus | Sex, saliva |
| Lymphocryptovirus | γ | Humans; mammals | B-lymphocytes | Glycoproteins | Budding | Nucleus | Nucleus | Saliva |
| Muromegalovirus | β | Rodents | Salivary glands | Glycoproteins | Budding | Nucleus | Nucleus | Contact |
The three mammalian subfamilies –Alpha-,Beta- andGamma-herpesviridae – arose approximately 180 to 220mya.[17] The major sublineages within these subfamilies were probably generated before the mammalian radiation of 80 to 60 mya. Speciations within sublineages took place in the last 80 million years probably with a major component of cospeciation with host lineages.[citation needed]
All the currently known bird and reptile species are alphaherpesviruses. Although the branching order of the herpes viruses has not yet been resolved, because herpes viruses and their hosts tend to coevolve this is suggestive that the alphaherpesviruses may have been the earliest branch.[citation needed]
The time of origin of the genusIltovirus has been estimated to be 200 mya while those of the mardivirus and simplex genera have been estimated to be between 150 and 100 mya.[18]
 | This sectionis missing information about latency mechanisms beyond CMV, e.g. HSV LAT and ICP-47; whether there is a common mechanism in the family. Please expand the section to include this information. Further details may exist on thetalk page.(November 2021) |
Herpesviruses are known for their ability to establish lifelong infections. One way this is possible is through immune evasion. Herpesviruses have many different ways of evading the immune system. One such way is by encoding a protein mimicking humaninterleukin 10 (hIL-10) and another is by downregulation of themajor 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 inhibitingpro-inflammatory cytokine synthesis. The cmvIL-10 protein has 27% identity with hIL-10 and only one conserved residue out of the nine amino acids that make up thefunctional 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 regulateIFN-γ,IL-1α,GM-CSF,IL-6 andTNF-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 regulatingHLA-G (non-classical MHC I). These two events allow for immune evasion by suppressing the cell-mediated immune response andnatural 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.[19]
It was found that cmvIL-10 functions through phosphorylation of theStat3 protein. It was originally thought that this phosphorylation was a result of theJAK-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 synthesis. The proposed mechanism is that cmvIL-10 activates PI3K which in turn activatesPKB (Akt). PKB may then activatemTOR, which may target Stat3 for phosphorylation on the S727 residue.[20]
Another one of the many ways in which herpes viruses evade the immune system is by down regulation ofMHC I andMHC 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 theendoplasmic reticulum (ER). The MHC cannot reach the cell surface and therefore cannot activate theT cell response. The MHCs can also be targeted for destruction in theproteasome orlysosome. The ER proteinTAP 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.[21]
Below are the nine distinct viruses in this family known to cause disease in humans.[22][23][24]
| Name | Synonym | Subfamily | Primary Target Cell | Syndrome | Site of Latency | Means of Spread |
|---|---|---|---|---|---|---|
| HHV‑1 | Herpes simplex virus-1 (HSV-1) | α (Alpha) | Mucoepithelial | Oral and/orgenital herpes,herpetic gingivostomatitis,pharyngitis,eczema herpeticum,herpetic whitlow,herpes simplex keratitis,erythema multiforme,encephalitis, as well as otherherpes simplex infections | Neuron (sensory ganglia) | Close contact (oral orsexually transmitted infection) |
| HHV-2 | Herpes simplex virus-2 (HSV-2) | α | Mucoepithelial | Oral and/orgenital herpes,herpetic gingivostomatitis,pharyngitis,eczema herpeticum,herpetic whitlow,herpes simplex keratitis,erythema multiforme,Mollaret's meningitis, as well as other herpes simplex infections | Neuron (sensory ganglia) | Close contact (oral orsexually transmitted infection) |
| HHV-3 | Varicella zoster virus (VZV) | α | Mucoepithelial | Chickenpox andshingles | Neuron (sensory ganglia) | Respiratory and close contact (includingsexually transmitted infection) |
| HHV-4 | Epstein–Barr virus (EBV)Lymphocryptovirus | γ (Gamma) | B cells andepithelial cells | Severe mosquito bite allergy,Epstein-Barr virus-positive reactive lymphoid hyperplasia,Infectious mononucleosis,Burkitt's lymphoma,Epstein–Barr virus-positive Hodgkin lymphoma,extranodal NK/T cell lymphoma, nasal type,Epstein–Barr virus-associated aggressive NK cell leukemia,CNS lymphoma in AIDS patients,post-transplant lymphoproliferative syndrome (PTLD),nasopharyngeal carcinoma, HIV-associatedhairy leukoplakia,multiple sclerosis | B cell | Close contact, transfusions, tissue transplant, and congenital |
| HHV-5 | Cytomegalovirus (CMV) | β (Beta) | Monocytes andepithelial cells | Infectious mononucleosis-like syndrome,[25]retinitis | Monocyte, and ? | Saliva, urine, blood, breast milk |
| HHV-6A and 6B | Roseolovirus | β | T cells and ? | Sixth disease (roseola infantum orexanthem subitum) | T cells and ? | Respiratory and close contact? |
| HHV-7 | β | T cells and ? | drug-induced hypersensitivity syndrome, encephalopathy, hemiconvulsion-hemiplegia-epilepsy syndrome, hepatitis infection, postinfectious myeloradiculoneuropathy, pityriasis rosea, and the reactivation of HHV-4 (EBV), leading to "mononucleosis-like illness" | T cells and ? | ? | |
| HHV-8 | Kaposi's sarcoma-associated herpesvirus (KSHV), a type ofRhadinovirus | γ | Lymphocyte and other cells | Kaposi's sarcoma,primary effusion lymphoma, some types of multicentricCastleman's disease | B cell | Close contact (sexual), saliva? |
In addition to the herpesviruses consideredendemic in humans, some viruses associated primarily with animals may infect humans. These arezoonotic infections:
| Species | Type | Synonym | Subfamily | Human Pathophysiology |
|---|---|---|---|---|
| Macaque monkey | CeHV-1 | Cercopithecine herpesvirus 1, (monkey B virus) | α | Very unusual, with only approximately 25 human cases reported.[26] Untreated infection is often deadly; sixteen of the 25 cases resulted in fatalencephalomyelitis. At least four cases resulted in survival with severe neurologic impairment.[26][27] Symptom awareness and early treatment are important for laboratory workers facing exposure.[28] |
| Mouse | MuHV-4 | Murid herpesvirus 68 (MHV-68) | γ | Zoonotic infection more common in laboratory workers handling infected mice.[29][30] ELISA tests show factor-of-four (x4)false positive results, due to antibody cross-reaction with other herpesviruses.[29] |
Inanimal virology, the best known herpesviruses belong to the subfamilyAlphaherpesvirinae. Research onpseudorabies virus (PrV), the causative agent ofAujeszky'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, whereasbovine herpesvirus 1, the causative agent ofbovine infectious rhinotracheitis andpustular vulvovaginitis, is analyzed to elucidate molecular mechanisms of latency. Theavian infectious laryngotracheitis virus is phylogenetically distant from these two viruses and serves to underline similarity and diversity within theAlphaherpesvirinae.[2][3]
Research is currently ongoing into a variety of side-effect or co-conditions related to the herpesviruses. These include:[citation needed]
