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White Footed Mice, Peromyscus leucopus, Sin Nombre-like hantavirus host
Deer mouse, Peromiscus maniculatus,  Sin Nombre hantavirus host

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Hantavirus

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Definition

A genus of the family BUNYAVIRIDAE causing HANTAVIRUS INFECTIONS, first identified during the Korean war. Infection is found primarily in rodents and humans. Transmission does not appear to involve arthropods. HANTAAN VIRUS is the type species. (MeSH, Year introduced: 1992)

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Taxonomy

Lineage

viruses - ssRNA viruses - ssRNA negative-strand viruses - Bunyaviridae - Hantavirus -

Family Bunyaviridae and genus Hantavirus

Hantaviruses constitute a distinct genus (Hantavirus) in the family Bunyaviridae. They are enveloped, negative-strand RNA viruses with a tripartite genome.

The categorization of hantaviruses as belonging to the family Bunyaviridae is due in part to the consistent presence of three genomic RNA segments that are circularized in vivo as a result of the presence of terminal complementary nucleotides that help fold the genome into a “hairpin” morphology, first described for the Uukuniemi phlebovirus.

Other genera in the family include Bunyavirus, Nairovirus, Phlebovirus, and Tospovirus. Bunyaviruses, Nairoviruses, Phleboviruses, and Tospoviruses are classical arboviruses (ARthropode-BOrn viruses) in that they are all transmitted through obligate intermediate arthropode vectors such as mosquitoes, ticks, phlebotomine flies, other arthropods, or thrips. Hantaviruses, however, are transmitted directly from an infected rodent to a naïve rodent via aerosolized urinary, fecal, or salivary secretions without the aid of an intermediate vector.

There are currently about 20 well-described hantaviruses, each of which is closely associated with a single rodent or insectivore host. Specific rodent-hantavirus pairs are so closely associated that it is generally believed that the rodent and its associated hantavirus have co-evolved. As a result of the long-standing co-evolution of rodent-hantavirus pairs, hantaviruses do not cause overt clinical disease in their well-adapted rodent hosts.

In the absence of any arthropod vector that would facilitate their transmission to possible alternative host species, hantaviruses developed a narrow host range. Phylogenetic analysis demonstrates that hantaviruses break into three distinct clades, each of which closely coincides with the subfamily of its rodent host.

In the latest (VIIth) Report of the International Committee on Taxonomy of Viruses (ICTV) the following four formal criteria are suggested to define distinct hantavirus species. According to these criteria, hantavirus species:

HTNV is the prototype species of the genus Hantavirus and remains until now the epidemiologically most important species in the genus.

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Brief facts

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Genome organization

Hantaviruses have tripartite (containing three parts) negative-sense single stranded RNA genome. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation.

The genome segments are designated:

Each of the genomic segments has a slightly mismatched, conserved, inverted repeat at its 3' and 5' ends. This allows the genomic segments to form a panhandle structure that is believed to play an important role in virus morphogenesis.

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Mechanisms of genetic diversity

RNA viruses show high mutation frequencies partly because of a lack of the proofreading enzymes that assure fidelity of DNA replication.

Analysis of the current collection of hantavirus genome sequences shows that the genetic diversity of hantaviruses is generated primarily by genetic drift, i.e. accumulation of point mutations and insertions/deletions of one or several nucleotides.

While mutation is the ultimate source of genetic variation, recombination can act on mutation to shape the genetic structure of populations.

Two distinct mechanisms can generate viral recombinant genomes:

Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by eukaryotes to accurately repair harmful breaks that occur on both strands of DNA and in process of meiosis. Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses.

To date, the strongest evidence for recombination in negative sense RNA viruses comes from hantaviruses. Phylogenetic analysis of the S segment indicated that the eastern Slovakian Tula hantavirus underwent homologous recombination and formed an independent lineage. Several studies reported recombination in Hantaan virus, Dobrava virus, Andes virus, and Puumala virus. Therefore, recombination appears to be a common occurrence in hantaviruses, relative to most other negative sense RNA viruses. This suggests there are unknown mechanisms contributing to hantavirus recombination.

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Virion morphology

Virion structure

Negative stained electron micrographs of hantaviruses show pleomorphic, enveloped virions that are approximately 100 nm in diameter. Virions have a short 5-10 nm fringe of peplomers, which gives them a "fuzzy" or tessellated ultrastructural appearance. While not unique, the appearance of hantaviruses is quite distinct.

Glycoproteins

Coded by the medium (M) segment, glycoproteins Gn (formerly, G1) and Gc (formerly, G2) are transmembrane proteins that are associated with the lipid envelope of the virion. The glycoproteins are believed to interact with host's integrin receptors to facilitate infection of endothelial cells, macrophages, and platelets.

N protein is the most abundant hantavirus protein found in the cytoplasm of infected cells. It is coded by the small segment (S) are associated with the hantavirus genome, coating each of the three genomic segments within the virion and forming ribonucleocapsids. Its transcript is detected in infected cells six hours post infection. N protein is responsible for encapsidation and packaging of the viral genome.

RNA-dependent RNA polymerase (RdRp)

The large (L) segment encodes a RNA-dependent RNA polymerase (RdRp). Several copies of the virus RdRp (~250 kDa) are believed to be packaged within each virion and associated with the virus ribonucleocapsids through non-covalent interactions. No proof-reading functions have been associated with the hantavirus polymerase protein, thus the viruses within the genus display tremendous genomic heterogeneity with nucleotide identities that can vary by as much as 50% between viruses within the Hantavirus genus. Because of its large molecular weight RdRp is difficult to express in bacteria, and thus remains the most uncharacterized protein in hantaviruses. RdRp mediates both transcription and replication of viral genome. During transcription RdRp synthesizes viral mRNA from negative sense vRNA template. During replication RdRp replicates vRNA genome via a cRNA intermediate. Thus it is likely that hantavirus RdRp has multiple activities, including endonuclease, replicase, transcriptase and RNA helix unwinding activities.

Hantavirus morphology

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Hantavirus life cycle

Hantavirus replication takes place in macrophages and vascular endothelial cells, especially in the lung and the kidney.

Basic stages:
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Hosts and transmission, epidemiology

Muridae family rodents are reservoirs for hantaviruses. Thottapalayam (TPMV) virus is an exception because it was isolated from an insectivorous shrew, Suncus murinus. TPMV was also the first hantavirus to be isolated in cell culture; however, it was not thought to be a hantavirus until a partial genomic sequence was determined in 1992 showing genetic homology with known hantaviruses.

Each of the currently recognized ~20 species of rodent-borne hantaviruses is predominately associated with a single specific rodent host in which it establishes a persistent, most likely lifelong, infection that does not cause any deleterious effects in their well-adapted rodent host species.

It is currently estimated that there are approximately 2,000 species of murid rodents, of which less than 100 have been thoroughly screened for hantaviruses, and only 22-23 different hantaviruses have been described. This means that roughly one quarter of rodents screened for hantaviruses are positive, and that approximately 1900 murid rodents have not been thoroughly tested for the presence of hantaviruses. Since hantaviruses are a newly emerging and recently recognized group of human pathogens, with case fatality rates as high as 50%, this certainly piques one's interest regarding how many species of hantaviruses might truly exist. As was experienced in the recent Sin Nombre outbreak in the U.S., many of these supposed hantaviruses may be an underappreciated causes of human disease.

In surveys of trapped rodents seroprevalences of up to 50% have been described for Seoul virus in rats, 5–16% for Puumala in bank voles and 2–7.7% for new world hantaviruses in rodents in North and South America. It is known that acutely infected rodents are transiently viremic with peak viremia occurring 7-14 days postinfection.

Transmission in rodents

In rodents, transmission seems to occur by close contact between infected and naïve rodents through aerosolized urine, feces. For example, urine appeared to be the mode of transmission of Seoul virus between rats housed in the same cages, and airborne spread of Hantaan could occur between A. agrarius when housed as far apart as 4 m. Transmission has also been suggested to occur through fighting, biting, and sexual behavior. There is no evidence to support vertical transmission as a common means of transmitting hantaviruses from an infected dam to her pups.

Cross-species transmission is a major process during spread, emergence, and evolution of RNA viruses. For example, ANDV is the predominant etiologic agent of HCPS in South America, and O. longicaudatus the main rodent reservoir. Spillover in at least four other rodent species that co-occur with the reservoir have been identified. In North America, spillover of Bayou virus (BAYV) may have occurred from the main reservoir O. palustris to S. hispidus, R. fulvescens, P. leucopus, and B. taylori. Hantavirus spillover is more likely to occur between sympatric (exist in the same geographic area and regularly encounter one another) host populations, and closely related species. An interesting exception is found between Oxbow virus (OXBV) and Asama virus (ASAV) in which a host-switch process seemed to have occurred between mammals belonging to two families (Talpidae and Soricidae), likely as a result of alternating and recurrent co-divergence of certain taxa through evolutionary time.

Transmission in humans

Similar to rodent mode of transmission, humans acquire hantaviruses primarily via the respiratory route through aerosolized rodent excreta (urine, feces). The infective dose is unknown but presumed to be low by analogy with transmission between rodent hosts and because persistently infected rodents do not excrete large amounts of virus. In the Americas, person-to-person transmission has not been observed for the majority of hantaviruses; however, cases of person-to-person transmission of ANDV have been reported, although rarely, in Argentina and Chile. Recent surveillance data showed PUUV RNA in saliva of patients; however, inhibitory substances in saliva may prevent the transmission of live virus.

There is significant risk of human occupational exposure to hantaviruses. Mammalogists and agricultural and forestry workers are at the highest risk of occupational exposure to hantaviruses. Personnel that work in laboratory animal facilities or scientists that trap or work with wild rodents or with murine cell lines are also at risk.

Other possible hosts

The recent reports on the detection of hantavirus specific antibodies in domestic animals, small mammals, and in wildlife together with the replication of hantaviruses in bovine aortic endothelial cells are further evidence that Rodentia, Insectivora, Lagomorpha, and Carnivora cannot be considered anymore as the only reservoir and/or transmission source for hantaviruses. The detection of hantavirus antigens in the lung suspension of different bird species captured in the far east region of Russia by ELISA is of particular importance in view of hantavirus transmission and ecology. The birds identified to be infected with hantaviruses belonged to the orders Columbiformes (pigeons), Passeriformes (song birds), Galliformes (chicken-like), Strigiformes (owls), and Ciconiformes (wading birds kike herons, storks). The confirmation of this discovery is still open.

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Diagnosis

Diagnosis of hantavirus infection in humans depends upon initial clinical suspicion raised by pulmonary or renal syndrome occurring after possible exposure to rodents and their secreta (outdoors, laboratory, field or agricultural work). A variety of other pathogens and noninfectious conditions may cause similar symptoms and need to be considered.

"Gold standard" for detection of known and as yet undiscovered hantaviruses is by reverse transcription-PCR (RT-PCR), which is highly sensitive especially if certain strain is suspected, but caution must be used in choosing appropriate primer sets and in interpreting results. However, laboratory diagnosis of acute hantavirus infection has to be primarily based on serology, since the viremia of human hantavirus infections is short-termed and viral RNA cannot be regularly detected in the blood or urine of patients in hospitals.

Serologic tests monitor antibody responses to a given agent; thus, actively replicating virus does not need to be present in the animals that are being tested to determine if exposure has occurred. A further benefit to using serologic tests is that antibody- negative carrier states have not been documented for the hantaviruses therefore, if an immunologically competent animal is infected it should develop a measurable antibody response.

Diagnosis of hantaviruses of unknown origin in humans as well as arbitrary animal hosts is very challenging due to their heterogeneity. Serologic tests, particularly the immunofluorescent antibody test (IFAT), have historically been the diagnostic test of choice for subtyping and classifying arboviruses and currently is a method of choice for identifying new members of the family Bunyaviridae.

The enzyme-linked immunosorbent assay (ELISA) is commonly used in diagnostic testing labs because it is rapid, sensitive and specific, and it is easily automated, making it a cost effective test. Many diagnostic ELISAs utilize recombinant nucleocapsid proteins as an antigen source, as the nucleocapsid protein is the most antigenic and cross-reactive of the four hantavirus proteins, and because use of a recombinant protein as the antigen source avoids the biohazard associated with handling intact infectious virus. A strip immunoblot assay has also been developed for the rapid diagnosis of SNV infections, which takes advantage of the immunogenicity of a recombinant, truncated, 59 amino acid N-terminal nucleocapsid protein. The strip immunoblot is both rapid and sensitive for the diagnosis of PUUV and SNV infections; however, it lacks sensitivity for detecting HTNV and SEOV infections.

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Disease and pathogenesis

There are two major clinical presentations of hantavirus infection — hemorrhagic fever with renal syndrome (HFRS) caused by Old World hantaviruses such as HTNV, SEOV, PUUV, and DOBV, found worldwide in various forms and hantavirus pulmonary syndrome (HPS), found only in the Americas. The latter emerged in the New World in May 1993 when a cluster of deaths occurred in the Four Corners area of the U.S. desert Southwest among a group of young, previously healthy individuals nearly one-half of whom died from fulminant pulmonary edema.

Both hantavirus syndromes in humans do not truly represent two clinically distinct diseases, rather they represent a continuum from renal disease in HFRS to pulmonary disease in HPS. For example, there are subclinical and clinical pulmonary sequelae to HFRS infection in humans, as well as the previously described renal complications that arise from HPS. This is most likely a result of the fact that hantaviruses infect and replicate primarily within endothelial cells, which are widely distributed. The particular cellular tropisms of individual hantaviruses are most likely responsible for the varying course and severity of human diseases that are seen.

Both syndromes appear to be produced by immune and inflammatory mediators that result in an enormous increase in vascular permeability. A critical feature of both syndromes is a transient (∼ 1–5 days) capillary leak involving the kidney and retroperitoneal space in HFRS and the lungs in HCPS. The resulting leakage is exudative in character, with chemical composition high in protein and resembling plasma.

The period between virus acquisition and onset of symptoms is 1-3 weeks depending on the virus.

Hemorrhagic fever with renal syndrome (HFRS)

HFRS is most commonly a disease found in the human population in Eurasia, is caused by Hantaan, Seoul, Dobrava, and Puumala viruses, and is associated with rodents of the subfamilies Murinae and Arvicolinae. From 150,000 to 200,000 cases of HFRS are diagnosed in China annually. Additionally, a significant but unknown number of cases are diagnosed in Korea and Russia each year. Several thousand cases are also reported in the Balkans, Western Europe, and Scandinavia. Further, sporadic cases of HFRS are reported worldwide due to the global distribution of the Norwegian rat (Rattus norvegicus).

The severity of disease varies with the virus and with human host characteristics. In HFRS, Hantaan and Dobrova/Belgrade tend to produce the most severe disease, with mortality rates of 5–35%, Puumala is the least severe (called nephropathia epidemica: NE) with a mortality rate of less than 1% and Seoul is intermediate in severity with a 1% mortality rate

The disease has distinct 5 stages:

Hantavirus pulmonary syndrome (HPS)

HPS is associated with pulmonary disease. Retrospective analysis indicates that HPS is not a new disease, simply that its etiology and case presentation were previously underappreciated. It is caused by a newly recognized clade of hantaviruses that have only been found in New World rodents of Sigmodontinae subfamily.

In HPS the site of vascular leakage is primarily in the lungs rather than the retroperitoneal space. In contrast to HFRS disease, the urinary system, including the kidneys, is largely unaffected in HPS. HPS is a more severe disease than HFRS, with a mortality rate of about 40%. Death generally results from shock, pulmonary edema, and cardiac complications with oxygen saturation rates frequently less than 90%.

Cases of HPS have been reported for the following American countries: the United States, Canada, Argentina, Bolivia, Brazil, Chile, Panama, Paraguay, and Uruguay.

The clinical course of HPS is divided into three periods:

Pathogenesis

Autopsy specimens from humans who died of HPS revealed higher than normal numbers of cytokine-producing cells in the lungs and spleens as assessed by immunohistochemical staining for interleukin (IL)- 1α, IL-1β, IL-2, IL-4, IL-6, tumor necrosis factor (TNF)-α, TNF- β, and interferon-γ. These findings have led to speculation that vascular endothelial injury associated with HPS and HFRS is not a direct result of viral replication, but rather is the result of the host inflammatory response to the virus. Hantavirus-specific CD4+ and CD8+ cytotoxic T lymphocytes have been isolated from pulmonary tissues of patients who died from HPS. These results clearly indicate that activated T cells are intimately involved in the pathogenesis of hantavirus infection. Further, the major histocompatibility (HLA) type of affected patients has also been associated with the clinical disease course, as might be expected in an immunopathologic disease. Yet exact mechanism of how hantaviruses induce HPS and HFRS is not clear.

Immunity

Several observations suggest that previously infected individuals are protected life-long from reinfection. There are no known re-infections with the homologous hantavirus. Closely related hantaviruses, such as Seoul and Hantaan viruses, seem to cross-protect against re-infection in experimental animals, and one might expect cross-protection among the hantaviruses derived from sigmodontine rodents.

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Treatment

Currently, there is no specific therapy available for both HFRS and HPS. Several drugs have been tried with various effects including IFN-α, steroids, and cyclophosphamide. Ribavirin treatment was shown to significantly reduce mortality rate when administered early after the onset of HFRS and is often used in treatment of HFRS in China. However, ribavirin was ineffective for the treatment of HPS in the cardiopulmonary stage.

The cornerstone of treatment remains supportive measures. The management must include early admission to an intensive care unit where blood and tissue oxygenation, cardiac output, central blood pressure and cerebral pressure can be monitored. Maintaining fluids balance is very important; it must be carefully monitored according to the patient's fluid status, amount of diuresis, and kidney function. Usually one or two hemodialysis sessions are needed for HFRS treatment, while mechanical ventilation when indicated and appropriate use of pressures are crucial to HPS patients.

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Prevention

Since hantaviruses are carried by rodents and spread via aerosol and biting, the central means for prevention of infection is the reduction of rodent exposure. Effective measures include rodent proofing of homes, proper storage of food, disinfection and removal of trapped rodents and their excreta.

Inactivated and recombinant vaccine strategies have been used for development of vaccines against hantaviruses. In Korea, a formalin-inactivated HTNV vaccine, Hantavax (Korea Green Cross, Seoul, Korea), that is produced from rodent brain–derived virus, is commercially available. Hantavax was shown to induce high titers of IgG-specific antibodies in almost 100% of human volunteers after three vaccinations accompanied by the production of neutralizing antibodies in approximately 80% of test individuals; however, the antibody titers declined very rapidly within months, and boosters yielded no satisfactory protection rates. In China, 4 million doses of five commercially available hantavirus vaccines are annually produced.

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Weather and climate change effects

Rodent population dynamics are affected by seasonal changes of weather and climate.

The following regulators of zoonotic virus prevalence and transmission were suggested:

These five factors can differentially impact the biology and ecology of the host-virus ecosystem and, consequently, the risk of disease transmission to humans. For example, disturbed rodent habitats, such as those caused by deforestation and extensive agriculture, may favor opportunistic or generalist species that may be reservoirs for hantaviruses. Environmental changes commonly decrease rodent diversity, which could enhance more host species interaction and, hence, more hantaviral transmission events within a single species. As a consequence, this may activate a cascade with a greater transmission of the virus among rodents, leading to a greater the risk of spillover of rodents with virus into human activities.

It can reasonably be concluded that climate change should influence hantaviruses through impacts on the hantavirus reservoir host populations. We can anticipate changes in the size and frequency of hantavirus outbreaks, the spectrum of hantavirus species and geographical distribution (mediated by changes in population densities), and species composition and geographical distribution of their reservoir hosts. The early effects of global warming have already been observed in different geographical areas of Europe. Elevated average temperatures in West-Central Europe have been associated with more frequent Puumala hantavirus outbreaks, through high seed production (mast year) and high bank vole densities. The US Four Corners outbreak in 1993 was preceded by a dramatic increase in rainfall associated with the 1992–1993 El Nin˜o. This led to increased rodent food resources and a focal 20-fold increase in the rodent population, followed by invasion of buildings by rodents, and an increased risk of human disease. On the other hand, warm winters in Scandinavia have led to a decline in vole populations as a result of the missing protective snow cover.

Increasing intensity and frequency of extreme climatic events, such as floods, droughts or hurricanes, represent extremely important contributory factors in the context of climate change and its impact on hantavirus disease in humans. A 30-year study of a desert rodent community affected by two major floods demonstrated that extreme climatic events can decimate resident populations, alter species composition and interspecific interactions, influence invasion dynamics and thereby result in a rapid, wholesale reorganization of the community. If hantavirus reservoir hosts form part of the affected community, dramatic changes in hantavirus incidence and species spectrum can be expected. Different hantavirus species could assume dominance, together with their natural host, whereas others could be eliminated from the affected geographical region. In such situations, currently unrecognized hantaviruses and reservoir hosts could replace the eliminated species. For example, shrews and the recently recognized shrew-associated hantaviruses, currently of unknown pathogenic potential, might be better adapted to the new climatic conditions.

In conclusion, it is difficult to predict how extensive the climate change effects will be. Nevertheless, hantaviruses will remain a significant public health threat in the near future.

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References

  1. Hantavirus - free articles in PubMed
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Further reading

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