| Orthopoxvirus | |
|---|---|
Virus classification | |
| (unranked): | Virus |
| Realm: | Varidnaviria |
| Kingdom: | Bamfordvirae |
| Phylum: | Nucleocytoviricota |
| Class: | Pokkesviricetes |
| Order: | Chitovirales |
| Family: | Poxviridae |
| Subfamily: | Chordopoxvirinae |
| Genus: | Orthopoxvirus |
| Species | |
Orthopoxvirus is a genus ofviruses in the familyPoxviridae and subfamilyChordopoxvirinae. Vertebrates, including mammals and humans, andarthropods serve as natural hosts. There are 12 species in this genus. Diseases associated with this genus includesmallpox,cowpox, horsepox,camelpox, andmpox.[1][2] The most widely known member of the genus isVariola virus, which causes smallpox. It was eradicated globally by 1977, through the use ofVaccinia virus as avaccine. The most recently described species is theBorealpox virus, first isolated in 2015.[3]
Orthopoxviruses are enveloped with brick-shaped geometries and virion dimensions around 200 nm wide and 250 nm long.[1]
Member viruses have linear double-stranded DNA genomes around 170–250kb in length.[1]
Viral replication is cytoplasmic. Entry into the host cell is achieved by attachment of the viral proteins to hostglycosaminoglycans (GAGs), which mediate cellularendocytosis of the virus. Fusion of theviral envelope with the plasma membrane releases theviral core into the hostcytoplasm. Expression of early-phase genes by viralRNA polymerase begins at 30 minutes after infection. The viral core is completely uncoated as early expression ends, releasing the viral genome into the cytoplasm. At this point, intermediate genes are expressed, triggering genomic DNA replication by the viralDNA polymerase about 100 minutes post-infection. Replication follows the DNA strand displacement model. Late genes are expressed from 140 min to 48 hours postinfection, producing all viral structural proteins. Assembly of progeny virions begins in cytoplasmic viral factories, producing a spherical immature particle. This virus particle matures into the brick-shaped intracellular mature virion, which can be released upon celllysis, or can acquire a second membrane from theGolgi apparatus and bud as extracellular enveloped virions. In this latter case, the virion is transported to the plasma membrane viamicrotubules.[1]
Natural hosts of orthopoxviruses aremammals andarthropods. Member viruses are transmitted by respiratory droplets, contact, andzoonosis.[1]
Some orthopoxviruses, including the mpox, cowpox, andbuffalopox viruses, have the ability to infect non-reservoir species. Others, such asectromelia andcamelpox viruses, are highly host-specific. Vaccinia virus, maintained in vaccine institutes and research laboratories, has a very wide host range. Vaccine-derived vaccinia has been found replicating in the wild in Brazil, where it has caused infections in rodents, cattle, and even humans.[4] Following the eradication of variola virus, camelpox has become one of the most economically importantOrthopoxvirus infections, because many subsistence-level nomadic communities depend heavily on camels.[citation needed]
The genus contains the following species, listed by scientific name and followed by the exemplar virus of the species:[5][6]
The relatedBorealpox virus, also known as Alaskapox virus, has not been classified as of 2024.[3][7]
Among the path of evolution of theOrthopoxvirus species, many genes are truncated (but still functional), fragmented, or lost. Cowpox strains tend to have the most intact genes. Predicting thephylogeny by sequence or by gene content produces somewhat different results:[8]
| By sequence | By gene content | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Some of the differences in the two trees are attributed to the procedure of passage in producing vaccinia strains. TheModified vaccinia Ankara strain in this regard has much gene loss related toin vitro passage, and horsepox being a vaccinia strain found in a natural outbreak has less.[8]
Following the eradication of the human-specific variola virus (smallpox), all humanOrthopoxvirus infections arezoonoses.[9] Mpox occurs naturally only in Africa, particularly in theDemocratic Republic of the Congo.[10] However, human andprairie dog cases have occurred in the US due to contact with animals imported fromGhana,[11] while in May 2022 anoutbreak of mpox began spreading globally. Cowpox only occurs in Europe and adjacent Russian states, and despite its name, occurs only rarely in cattle. One common host is thedomestic cat, from which human infections are most often acquired.[12][13] Cowpox virus has also infected a variety of animals in European zoos, such aselephants, resulting in human infection.[14]
Aerosols of concentrated virus may result inOrthopoxvirus infection, especially in unimmunized individuals.[15] In addition,needle sticks with concentrated virus or scratches from infected animals may result in local infection of the skin even in immunized individuals. Cowpox infection in Europe is an occupational hazard for veterinary workers, and to a lesser extent, farm workers.[13]
The initial symptoms ofOrthopoxvirus infection includefever,malaise, head and body aches, and occasionallyvomiting. With the exception of mpox infection, one lesion is the norm, although satellite lesions may be produced by accidental autoinoculation. Individuallesions, surrounded by inflammatory tissue, develop and progress throughmacules,papules,vesicles, andpustules, and eventually become dry crusts. (Lesions alone are not diagnostic forOrthopoxvirusinfection and may be mistaken for zoonoticParapoxvirus infections,anthrax orHerpesvirus infections.[13]) With severe infections, severeedema anderythema may affect large areas of the body.Encephalitis (alteration of mental status and focal neurologic deficits),myelitis (upper- and lower-motorneuron dysfunction, sensory level, and bowel and bladder dysfunction), or both may result fromOrthopoxvirus infection. Rarely, orthopoxviruses may be detected incerebrospinal fluid.[citation needed]
Regarding specificOrthopoxvirus infections, human mpox most resembles mild smallpox.[10] Human cowpox is a relatively severe localized infection. A survey of 54 cases reported three cases of generalized infection, including one death.[13]
Vaccinia-specificimmunoglobulins may be administered to infected individuals. The only product currently available for treatment of complications ofOrthopoxvirus infection is vaccinia immunoglobulin (VIG), which is an isotonic sterile solution of the immunoglobulin fraction ofplasma from persons vaccinated with vaccinia virus. It is effective for treatment of eczema vaccinatum and certain cases of progressive vaccinia. However, VIG is contraindicated for the treatment of vaccinialkeratitis. VIG is recommended for severe generalized vaccinia if the patient is extremely ill or has a serious underlying disease. VIG provides no benefit in the treatment ofpostvaccinal encephalitis and has no role in the treatment of smallpox. Current supplies of VIG are limited, and its use is reserved for treatment of vaccine complications with serious clinical manifestations. The recommended dosage of the currently available VIG is 0.6 ml/kg of body weight. VIG must be administered intramuscularly and is ideally administered as early as possible after the onset of symptoms. Because therapeutic doses of VIG might be substantial (e.g., 42 ml for a person weighing 70 kg), the product may be administered in divided doses over a 24- to 36-hour period. Doses can be repeated, usually at intervals of 2–3 days, until recovery begins (i.e., no new lesions appear). The CDC is currently the only source of VIG for civilians.[citation needed]
Certain antiviral compounds such astecovirimat (ST-246)[16] have been reported to be 100% active against vaccinia virus or other orthopoxvirusesin vitro and among test animals. Tecovirimat has been granted orphan drug status by theFood and Drug Administration (FDA) and is currently under study to determine its safety and effectiveness in humans. Another example isbrincidofovir. In June 2021, the FDA approved this drug for the treatment of smallpox in humans, making it the first drug approved for an effectively extinctmechanism of action. The decision followed a priority review by the agency, motivated by growing concern of potentialbioweapon development. Since the target virus is eradicated the efficacy could not be directly verified but was inferred via proxy, animal survival following infection by related species ofOrthopoxvirus. In contrast, safety data was available from trials of the drug in treatingCytomegalovirus infections in humans.[17]
Imatinib, a compound approved by the FDA for cancer treatment, has been shown to limit the release of extracellular enveloped virions and to protect mice from a lethal challenge with vaccinia.[18] Currently, imatinib and related compounds are being evaluated by the CDC for their efficacy against variola virus and mpox virus.
In the summer of 2017, researchers at theUniversity of Alberta recreated horsepox via lab synthesis to conduct research intousing viruses to treat cancer.[19]