Hantavirus

Hantaviruses are negative sense RNA viruses in the Bunyaviridae family. Humans may be infected with hantaviruses through rodent bites, urine, saliva or contact with rodent waste products. Some hantaviruses cause potentially fatal diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), but others have not been associated with human disease. HPS cannot be transmitted person-to-person. The name hantavirus is derived from the Hantan River area in South Korea, which provided the founding member of the group: Hantaan virus (HTNV), isolated in the late 1970s by Ho-Wang Lee and colleagues. HTNV is one of several hantaviruses that cause HFRS, formerly known as Korean hemorrhagic fever.

History
The hantaviruses are a relatively newly discovered genus of viruses. Several thousand United Nations soldiers became ill with "Korean haemorrhagic fever" (now called HFRS) during the Korean War. This outbreak sparked a 25-year search for the etiologic agent. The isolation of Hantaan virus, or HTNV, was reported by Ho-Wang Lee of South Korea in 1978.

In 1993, an outbreak of Hantavirus pulmonary syndrome (HPS, see below) 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, Peromyscus maniculatus, was first identified by Terry Yates, a professor at the University of New Mexico. In addition to Hantaan virus and Sin Nombre virus, several other hantaviruses have been implicated as etiologic agents for either HFRS or HPS. Other identified hantaviruses have not been associated with disease.

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 G1 and 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 39-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 59 terminal sequence and is distinct from those of the other four genera in the family. These sequences may form panhandle structures which seem likely to play a role in replication. 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 100 nanometres (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 G1 and G2, 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 is 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.

Prevalence
Regions especially affected by HFRS 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 HCPS include Patagonian Argentina, Chile, Brazil, the United States, Canada, and Panama, where a milder form of disease that spares the heart has been recognized. The two agents of HCPS 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. In the U.S., minor cases of HCPS include 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 - 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), and North Dakota (12). With only 11 cases, Oregon has a notably lower attack rate overall and relative to population, compared to other Western states.

Haemorrhagic fever with renal syndrome
Hantavirus has an incubation time of two to four weeks in humans before symptoms of infection occur. The symptoms of HFRS can be split into five phases:


 * Febrile phase: Symptoms include fever, chills, sweaty palms, diarrhea, malaise, headaches, nausea, abdominal and back pain, respiratory problems such as the ones common in the influenza virus, as well as gastro-intestinal problems. These symptoms normally occur for three to seven days and arise about two to three weeks after exposure.
 * Hypotensive phase: This occurs when the blood platelet levels drop and symptoms can lead to tachycardia and hypoxemia. This phase can last for 2 days.
 * Oliguric phase: This phase lasts for three to seven days and is characterised by the onset of renal failure and proteinuria occurs.
 * Diuretic phase: This is characterized by diuresis of three to six litres per day, which can last for a couple of days up to weeks.
 * Convalescent phase: This is normally when recovery occurs and symptoms begin to improve.

Formerly known as Korean hemorrhagic fever, HFRS is the term accepted by the World Health Organization.

Hantavirus (cardio-)pulmonary syndrome
Hantavirus pulmonary syndrome (HPS) is an often fatal disease caused by hantavirus infection. The symptoms are very similar to those of HFRS and include tachycardia and tachypnea. Additionally, patients will develop difficulty breathing, coughing and shortness of breath. Such conditions can lead to a cardiopulmonary phase, where cardiovascular shock can occur, and hospitalization of the patient is required. HPS was first recognized in 1993 in the southwest of the United States by Bruce Tempest MD, and was originally called "Four Corners disease". It has since been identified throughout the United States. Although rare, HPS is fatal in up to 60% of cases. Rodent control in and around the home remains the primary strategy for preventing hantavirus infection. People suspecting illness are encouraged to contact their local health department.

Weaponization
Korean hemorrhagic fever (Hantavirus) was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before suspending its biological weapons program.

Prevention and treatment
There is no known antiviral treatment, but natural recovery from the virus is possible. Patients with suspected hantavirus are usually admitted to hospital and given oxygen to help them breathe. 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, laying down poisons or using natural predators such as cats in the home.