Hantavirus

Hantaviruses are single-stranded, enveloped, negative sense RNA viruses in the Bunyaviridae family. They normally infect rodents and don't cause disease in these hosts. Humans may become infected with hantaviruses through contact with rodent urine, saliva, or feces. Some strains of hantaviruses cause potentially fatal diseases in humans, such as Hantavirus hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), while others have not been associated with known human disease.

Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement, but recent human-to-human transmission has been reported with the Andes virus in South America.

Hantavirus is named for the Hantan River area in South Korea where an early outbreak was observed. The virus was isolated in the late 1970s by Karl M. Johnson and Ho-Wang Lee.

History

The hantaviruses are a relatively newly discovered genus of viruses. An outbreak of Korean Hemorrhagic Fever among American and Korean soldiers during the Korean War (1950â€"1953) was later found to be caused by a hantavirus infection. More than 3000 troops became ill with symptoms that included renal failure, generalized hemorrhage, and shock. It had a 10% mortality rate. This outbreak sparked a 25-year search for the etiologic agent. Ho-Wang Lee, a South Korean virologist, Karl M. Johnson, an American tropical 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 the similar symptoms which overlap with Hantavirus pulmonary syndrome (HPS, see below), several scientists have theorised that the virus may have been the cause of the disease. The hypothesis was criticised because sweating sickness was recorded as being transmitted 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, in Spanish, "Virus sin nombre", for "nameless virus"). Its rodent host, the Deer mouse (Peromyscus maniculatus), was first identified by Terry Yates, a professor at the University of New Mexico.

Two major clinical syndromes

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 Bunyaviridae. It is also known as Korean hemorrhagic fever, epidemic hemorrhagic fever, and nephropathis epidemica. The species that cause HFRS include Hantaan River, Dobrava-Belgrade, Saaremaa, Seoul, and Puumala. It is found in Europe, Asia, and Africa.

In hantavirus induced hemorrhagic fever, incubation time is between two to four weeks in humans before symptoms of infection present. Severity of symptoms depends on the viral load.

Hantavirus pulmonary syndrome

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 Sin Nombre virus carried by deer mice. Prodromal symptoms include flu-like symptoms such as fever, cough, myalgia, headache, and lethargy. It is characterized by a sudden onset of shortness of breath with rapidly evolving pulmonary edema that is often fatal despite mechanical ventilation and intervention with potent diuretics. It has a fatality rate of 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.

Epidemiology

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 Patagonia Argentina, Chile, Brazil, the United States, Canada, and Panama.

Asia

In China, the Korean Peninsula, and Russia, hemorrhagic fever with renal syndrome is caused by Hantaan, Puumala and Seoul viruses. Korean Hemorrhagic Fever was first documented during the Korean War when American troops became ill.

South America

The two agents of HPS in South America are Andes virus (also called Oran, Castelo de Sonhos, Lechiguanas, Juquitiba, Araraquara, and Bermejo viruses, among many other synonyms), which is the only hantavirus that has shown (albeit uncommonly) an interpersonal form of transmission, and 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.

North America

In the U.S., minor cases of HPS include Sin Nombre virus, New York virus, Bayou virus, and possibly Black Creek Canal virus.

In the United States, as of July 2010 eight states had reported 30 or more cases of Hantavirus since 1993 â€" New Mexico (84), Colorado (70), Arizona (62), California (42), Washington (41), Texas (37), Utah (31) and Montana (30). Other states reporting a significant number of cases include Idaho (16), Kansas (15), South Dakota (15), North Dakota (12) and Oregon (11).

In late August and early September of 2012, eight new cases of Hantavirus were confirmed, including three deaths, in the Curry Village area of Yosemite National Park. On Long Island, David Hartstein, a chiropractor, died in June 2011, after contracting hantavirus. His story is featured in the HBO documentary Hard Times, Lost on Long Island.

In addition to infecting rodents hantaviruses are known to be carried by shrews (order Soricomorpha, family Soricidae) and moles (family Talpidae).

In Mexico a number of rodents have been found to carry hantaviruses: Megadontomys thomasi, Neotoma picta, Peromyscus beatae, Reithrodontomys megalotis and Reithrodontomys sumichrasti.

In Canada, there was one confirmed death in Northern British Columbia in January, 2013 and at least one confirmed death in Kindersley, Saskatchewan, in June 2013. Another death in the Kindersley area (June 2013) may also be linked to Hantavirus. One confirmed case (July 2013) in Burr, Saskatchewan (near Kindersley); the patient was gravely ill but survived.

Europe

In Europe three hantaviruses - Puumala, Dobrava and Saaremaa viruses - are known to cause haemorrhagic 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 while similar often also have haemorrhagic complications. There are few reports of confirmed Saaremaa infections but these appear to be similar to those caused by Puumala and less pathogenic than Dobrava.

Puumala is carried by its rodent host, the bank vole (Clethrionomys glareolus) and is present through most of Europe excluding the Mediterranean region. Dobrava and Saaremaa carried respectively by the yellow necked mouse (Apodemus flavicollis) and the striped field mouse (Apodemus agrarius) are reported mainly in eastern and central Europe.

Africa

A novel hantavirus, Sangassou virus has been isolated in Africa that causes hemorrhagic fever with renal syndrome.

Prevention and treatment

There is no known antiviral treatment, but natural recovery from the virus is possible with supportive treatment. Patients with suspected hantavirus are usually admitted to the hospital and given oxygen and mechanical ventilation support to help them breathe during the acute pulmonary stage. As the virus can be transmitted by rodent saliva, excretia, 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, laying down poisons or using natural predators such as cats in the home.

Leptospirosis causes similar symptoms and is also carried by rodent vectors, but it is due to a bacterial spirochete rather than a virus. Presumptive treatment of leptospirosis with penicillin (and other) antibiotics is often started for severe symptoms when a diagnostic dilemma between the two diseases is encountered.

Virology

Classification

Hantaviruses are Bunyaviruses. The Bunyaviridae family is divided into five genera: Orthobunyavirus, Nairovirus, Phlebovirus, Tospovirus, and Hantavirus. Like all members of this family, hantaviruses have genomes comprising three negative-sense, single-stranded RNA segments, and so are classified as negative sense RNA viruses. Members of other Bunyaviridae family genera are generally arthropod-borne viruses, but hantaviruses are thought to be transmitted to humans mainly through inhalation of aerosolized rodent excreta or rodent bites.

Genome

Like other members of the bunyavirus family, hantaviruses 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 Bunyaviridae, 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 structures 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.

Virions

Hantavirus virions are about 120-160 nanometers (nm) in diameter. The lipid bilayer of the viral envelope is about five 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 six 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 Bunyaviridae.

Life cycle

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. Subsequent to 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 (aka 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.

Pathogenesis

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 show up around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) will include difficulty breathing, shortness of breath and coughing.

Transmission

The species that cause hantavirus hemorrhagic fever have not been shown to transfer from person to person. Transmission by aerosolized rodent excreta still remains the only known way the virus is transmitted 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 patient-care workers in African hospitals. But those viruses do not transfer readily in the modern hospital setting with universal precautions. Fomite transfer has not been shown in the hantaviruses in either the hemorrhagic or pulmonary forms.

Evolution

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. However, recent findings have led to scientific debate and 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, hantaviruses have been found in multiple species of shrews and moles.

Taking into account the inconsistencies in the theory of coevolution, Ramsden et al. (2009) have proposed 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. Ulrich et al. (2010) have proposed that the observed 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, Yanagihara et al. (2011) have proposed that the evolutionary history of the hantavirus consists of a complex mix of both host switching and codivergence and suggest that ancestral shrews or moles rather than rodents may have been the early original hosts of ancient hantaviruses.

A Bayesian analysis suggests 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 500â€"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 500â€"600 years ago in Central America. These species 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.

Vaccine Research

The Korean Army is one of the largest consumers of the hantavirus vaccine, second only to public health centers. There are more than 20 recognized hantaviruses, some of which are associated with one of two serious human diseases: hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Efforts are continuing to develop safe and effective hantavirus vaccines. Several classical and molecular vaccine approaches are in pre-clinical stages of development. The development of hantavirus vaccines is hampered by the lack of adequate animal models of hantavirus-associated disease. No specific antiviral therapy is yet available. No hantavirus vaccine has been approved for use in the US, and no WHO-approved vaccine has gained widespread acceptance.