An orthohantavirus (or hantavirus) is a single-stranded, enveloped, negative-sense RNA virus in the family Hantaviridae of the order Bunyavirales. These viruses normally infect rodents, but do not cause disease in them. Humans may become infected with hantaviruses through contact with rodent urine, saliva, or feces. Some strains cause potentially fatal diseases in humans, such as hantavirus hemorrhagic fever with renal syndrome (HFRS), or hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS), while others have not been associated with known human disease. HPS (HCPS) is a “rare respiratory illness associated with the inhalation of aerosolized rodent excreta (urine and feces) contaminated by hantavirus particles.”
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Transmission electron micrograph of Sin Nombre orthohantavirus
• Andes orthohantavirus
• Asama orthohantavirus
• Asikkala orthohantavirus
• Bayou orthohantavirus
• Black Creek Canal orthohantavirus
• Bowe orthohantavirus
• Bruges orthohantavirus
• Cano Delgadito orthohantavirus
• Cao Bang orthohantavirus
• Choclo orthohantavirus
• Dabieshan orthohantavirus
• Dobrava-Belgrade orthohantavirus
• El Moro Canyon orthohantavirus
• Fugong orthohantavirus
• Fusong orthohantavirus
• Hantaan orthohantavirus
• Jeju orthohantavirus
• Kenkeme orthohantavirus
• Khabarovsk orthohantavirus
• Laguna Negra orthohantavirus
• Luxi orthohantavirus
• Maporal orthohantavirus
• Montano orthohantavirus
• Necocli orthohantavirus
• Oxbow orthohantavirus
• Prospect Hill orthohantavirus
• Puumala orthohantavirus
• Rockport orthohantavirus
• Sangassou orthohantavirus
• Seewis orhtohantavirus
• Seoul orthohantavirus
• Sin Nombre orthohantavirus
• Thailand orthohantavirus
• Tigray orthohantavirus
• Tula orthohantavirus
• Yakeshi orthohantavirus
The cotton rat, Sigmodon hispidus, is a hantavirus carrier that becomes a threat when it enters human habitation in rural and suburban areas.
Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement; however, in 2005 and 2019, human-to-human transmission of the Andes virus was reported in South America.
Hantavirus is named for the Hantan River area in South Korea where an early outbreak was observed, and was isolated in 1976 by Ho-Wang Lee.
Signs and symptoms
Hemorrhagic fever with renal syndrome
Main article: Hantavirus hemorrhagic fever with renal syndrome
Hemorrhagic fever with renal syndrome (HFRS) is a group of clinically similar illnesses caused by species of hantaviruses from the family Hantaviridae. It is also known as Korean hemorrhagic fever, epidemic hemorrhagic fever, and nephropathia epidemica. The species that cause HFRS include Hantaan, Dobrava-Belgrade, Saaremaa, Seoul, and Puumala. It is found in Europe, Asia, and Africa.
In hantavirus-induced hemorrhagic fever incubation time is two to four weeks in humans before symptoms develop. Their severity depends on the viral load.
Hantavirus pulmonary syndrome
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Hantavirus pulmonary syndrome (HPS) is found in North, Central and South America. It is an often fatal pulmonary disease. In the United States, the causative agent is the Sin Nombre virus carried by deer mice. Prodromal symptoms include flu-like symptoms such as fever, cough, muscle pain, headache, and lethargy. It is characterized by a sudden onset of shortness of breath with rapidly evolving pulmonary edema that is often fatal despite intervention with mechanical ventilation and potent diuretics. The fatality rate is 36%.
Hantavirus pulmonary syndrome was first recognized during the 1993 outbreak in the Four Corners region of the southwestern United States. It was identified by Dr. Bruce Tempest. It was originally called “Four Corners disease,” but the name was changed to “Sin Nombre virus” after complaints by Native Americans that the name “Four Corners” stigmatized the region. It has since been identified throughout the United States. Rodent control in and around the home remains the primary prevention strategy.
Hantaviruses are bunyaviruses. The order Bunyavirales is divided into twelve families. Like all members of this order (except for the Arenaviridae), hantaviruses have genomes comprising three negative-sense, single-stranded RNA segments, and so are classified as negative sense RNA viruses. Members of other Bunyavirales families are generally arthropod-borne viruses, but hantaviruses are thought to be transmitted to humans mainly through inhalation of aerosolized rodent excreta, or rodent bites.
Like other members of Bunyavirales, orthohantaviruses are enveloped viruses with a genome that consists of three single-stranded, negative-sense RNA segments designated S (small), M (medium), and L (large). The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins Gn (formerly G1) and Gc (formerly G2).
The L RNA encodes the L protein, which functions as the viral transcriptase/replicase. Within virions, the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments.
As with other Bunyavirales, each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length.
No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role.
Hantavirus virions are about 120–160 nanometers (nm) in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate (heterodimerize) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface.
Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid and 2–7% carbohydrate. The density of the virions is 1.18 gram per cubic centimeter. These features are common to all members of the Hantaviridae family.
Entry into host cells is thought to occur by attachment of virions to cellular receptors and subsequent endocytosis. Nucleocapsids are introduced into the cytoplasm by pH-dependent fusion of the virion with the endosomal membrane. After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the ER–Golgi Intermediate compartments (ERGIC) through microtubular-associated movement resulting in the formation of viral factories at ERGIC.
These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching, the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions.
The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex, where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae. Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis.
The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing.
The viruses that cause hantavirus hemorrhagic fever have not been shown to transfer from person to person, except for Andes virus. For other species of hantavirus, aerosolized rodent excreta or rodent bites are the only known routes of transmission to humans. Similar negative-stranded RNA viruses, such as Marburg and Ebola hemorrhagic fevers, can be transmitted by contact with infected blood and body fluids, and are known to spread to healthcare workers in African hospitals, but do not transfer readily in a modern hospital setting with the appropriate precautions. Transmission through fomites (inanimate objects exposed to infection) has not been demonstrated in hantavirus disease in either the hemorrhagic or pulmonary forms.
Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution, although findings in 2008 led to new hypotheses regarding hantavirus evolution.
Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission (host switching) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of shrews and moles.
Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Soricomorpha, it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses.
A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the Arvicolinae and Murinae subfamilies originated in Asia 500–700 years ago. These subsequently spread to Africa, Europe, North America and Siberia possibly carried by their hosts. The species infecting the Neotominae subfamily evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America.
According to the CDC, the best prevention against contracting hantavirus is to eliminate or minimize contact with rodents in the home, workplace, or campsite. As the virus can be transmitted by rodent saliva, excretions, and bites, control of rats and mice in areas frequented by humans is key for disease prevention. General prevention can be accomplished by disposing of rodent nests, sealing any cracks and holes in homes where mice or rats could get in, setting up traps, or laying down poisons or using natural predators such as cats in the home.
The duration that hantaviruses remain infectious in the environment varies based on factors such as the rodent’s diet, temperature, humidity, and whether indoors or outdoors. The viruses have been demonstrated to remain active for two to three days at normal room temperature, while ultraviolet rays in direct sunlight kills them within a few hours. However, rodent droppings or urine of indeterminate age should always be treated as infectious.
Main article: Hantavirus vaccine
As of 2016, there is no FDA-approved, commercially available vaccine against hantavirus. A vaccine known as Hantavax has been under study since 1990. As of 2016, the development was in clinical phase 3 trial stage. This inactivated vaccine is thought not to be effective against European hantaviruses like the Puumala (PUUV) virus. A killed-virus vaccine is not being pursued because of the dangers associated with mass production under high containment as well as the unresolved questions about the efficiency of the vaccine. A number of labs have been working towards a vaccine that would deliver viral antigens by either DNA vectors or as recombinant proteins. As of 2016, these recombinant vaccines will not be available in the near future.
No WHO-approved vaccine has gained widespread acceptance, but the Korean Army is one of the largest consumers of a hantavirus vaccine, second only to public health centers.
Ribavirin may be a drug for HPS and HFRS but its effectiveness remains unknown, still, spontaneous recovery is possible with supportive treatment. People with suspected hantavirus infection may be admitted to the hospital, given oxygen and mechanical ventilation support to help them breathe during the acute pulmonary stage with severe respiratory distress. Immunotherapy, administration of human neutralizing antibodies during acute phases of Hantavirus, has only been studied in mice, hamsters, and rats. There are no reports of controlled clinical trials.
Hantavirus infections have been reported from all continents but Australia. Regions especially affected by hemorrhagic fever with renal syndrome include China, the Korean Peninsula, Russia (Hantaan, Puumala and Seoul viruses), and northern and western Europe (Puumala and Dobrava virus). Regions with the highest incidences of hantavirus pulmonary syndrome include Argentina, Chile, Brazil, the United States, Canada, and Panama.
In 2010, a novel hantavirus, Sangassou virus was isolated in Africa which causes hemorrhagic fever with renal syndrome.
In China, Hong Kong, the Korean Peninsula and Russia, hemorrhagic fever with renal syndrome is caused by Hantaan, Puumala and Seoul viruses.
As of 2005, there were no human infections reported in Australia, though rodents were found to carry antibodies.
In Europe two hantaviruses — Puumala and Dobrava-Belgrade viruses — are known to cause hemorrhagic fever with renal syndrome. Puumala usually causes a generally mild disease, nephropathia epidemica, which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications.
Puumala virus is carried by its rodent host, the bank vole (Clethrionomys glareolus), and is present throughout most of Europe, except for the Mediterranean region. There are four known Dobrava virus genotypes, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse (Apodemus flavicollis); genotypes Saaremaa and Kurkino in the striped field mouse (Apodemus agrarius), and genotype Sochi in the Black Sea field mouse (Apodemus ponticus).
In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections.
Although there are Sin Nombre virus-infected deer mice, the primary cause of the disease all across Canada, by June 2015, there had been only one documented case of hantavirus pulmonary syndrome in eastern Canada, with most cases in British Columbia, Alberta, Saskatchewan and Manitoba in the west. There were a total of 109 confirmed cases; about 30% of those infected died. In Canada “[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities.”
The first confirmed death was in northern British Columbia in January, 2013 and another in Kindersley, Saskatchewan, in June 2013.
In the United States, minor cases of HPS include Sin Nombre orthohantavirus, New York orthohantavirus, Bayou orthohantavirus, and possibly Black Creek Canal orthohantavirus.
As of January 2017, 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River. The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death.
In Mexico, rodents have been found to carry hantaviruses include Thomas’s giant deer mouse (Megadontomys thomasi), the pack rat Neotoma picta, Orizaba deer mouse (Peromyscus beatae), Western harvest mouse (Reithrodontomys megalotis) and Sumichrast’s harvest mouse (Reithrodontomys sumichrasti).
Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for “Castle of Dreams”, Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus, an extremely close relative of the previously known Rio Mamore virus.
Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus.
In March 2020, a man from Yunnan tested positive for Hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus.
The hantaviruses are a relatively newly discovered genus of viruses. An outbreak of hemorrhagic fever among American and Korean soldiers during the Korean War (1950–1953) was caused by a hantavirus infection. More than 3000 troops became ill with symptoms that included kidney failure, generalized hemorrhage, and shock. It had a 10% mortality rate. Hantavirus was named for the Hantan River area in South Korea. This outbreak sparked a 25-year search for the etiologic agent. Ho-Wang Lee, a South Korean virologist, and his colleagues isolated Hantaan virus in 1976 from the lungs of striped field mice.
In late medieval England a mysterious sweating sickness swept through the country in 1485 just before the Battle of Bosworth Field. Noting that the symptoms overlap with hantavirus pulmonary syndrome (see above), several scientists have theorized that the virus may have been the cause of the disease. The hypothesis was criticized because sweating sickness was recorded as being transmitted from human to human, whereas hantaviruses were not known to spread in this way. Limited transmission via human-to-human contact has since been shown in Hantavirus outbreaks in Argentina.
In 1993, an outbreak of hantavirus pulmonary syndrome occurred in the Four Corners region in the southwestern United States. The viral cause of the disease was found only weeks later and was called the Sin Nombre virus (SNV), or in Spanish, “virus sin nombre”, meaning “nameless virus”. The host was first identified as the deer mouse (Peromyscus maniculatus) by Terry Yates, a professor at the University of New Mexico.