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Hantaviruses are thought to have appeared in humans in China over 1000 years ago, but gained attention when over 3000 United Nations and US soldiers became infected near the Hantaan River during the Korean War. Hantaan virus (HTNV) was identified as the causative agent in 1978. Currently, 21 different species and more than 30 different serotypes have been identified. The virus sporadically appears in human populations all over the world. Sin Nombre, the first pathogenic New World hantavirus, infected people in the Four Corners region of the southwestern US in the early 1990s. Each year hantaviruses are responsible for approximately 300 cases of disease in the Americas with mortality rates of up to 50% (Muranyi et al. 3669). The high mortality rate of this infection makes it crucial to understand the viral structure, life cycle, and method of transmission and pathogenesis in order to find ways to treat and prevent it.
Hantaviruses are members of the Bunyaviridae family and are single-stranded, negative-sensed viruses (Muranyi et al. 3669). This type of genome places them in Class V of the Baltimore classification system (Parilla). The virus is spherical and approximately 100 nanometers in diameter. It is enclosed in a lipid envelope that has two embedded surface glycoproteins, G1 and G2. Inside the envelope are three segments of single-stranded, negative-sensed RNA. The smallest strand, designated S (small) encodes for the nucleocapsid protein, which along with the three RNA segments and polymerase proteins forms three helical nucleocapsids. The M (medium) strand encodes for the surface glycoproteins and the L (large) strand encodes for an RNA-dependent RNA polymerase. (Muranyi et al. 3669). This same protein, L protein, also seems to function as an endonuclease (http://www.cdc.gov/ncidod/ diseases/hanta/hps/noframes/phys/virology.htm).
Hantaviruses target macrophages and vascular endothelial cells within the human host. Like most RNA viruses, they replicate in the cytoplasm of the host cell. Attachment is made via viral surface glycoproteins and avb3 integrins on the host cell surface. The virion enters the cell through endocytosis and pH-dependent fusion occurs with the endosome membrane, releasing the nucleocapsids into the cytoplasm. Once inside the cytoplasm, the virionââ‚¬â„¢s negative-sensed RNA must be copied into complimentary plus-sense mRNA before proteins can be made (Muranyi et al. 3672). The L protein cleaves the caps from cellular mRNA to create primers that can initiate transcription of viral mRNA (http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/ virology.htm). The L protein also functions as an RNA-dependent RNA polymerase and allows for replication of the viral RNA genome segments. Translation of the nucleocapsid proteins and the RNA polymerases occur at free host ribosomes, whereas translation of the G1 and G2 glycoproteins occurs in the endoplasmic recticulum. The glycoproteins are then transported to the Golgi complex where they are picked up by newly formed virions budding into the Golgi cisternae. Finally, the virus is transported to the plasma membrane in secretory vesicles and egress is via exocytosis (Muranyi et al. 3672).
Humans can acquire hantavirus by inhaling aerosolized excretions from an infected rodent, the natural reservoir for the virus (Muranyi et al. 3669). Person-to-person transmission of the virus has been documented in an outbreak of the Andes Sout strain in Argentina but humans are normally considered a dead-end host. The two main diseases that hantaviruses cause in humans are hemorrhagic fever with renal syndrome (HFRS) and human pulmonary syndrome (HPS) (Muranyi et al. 3670).
The progression of HPS can be categorized into three stages: prodromal, cardio-pulmonary, and convalescent. The prodromal phase is marked by flu-like symptoms such as fever, headache, and myalgia. Patients in the cardiopulmonary phase present with severe respiratory difficulty caused by edema and hypotension. During this phase, rapid breakdown of the skeletal muscle, rhabdomyolysis, is common. Blood tests show an increase in the concentration of red blood cells with a decrease in plasma and platelets. White blood cell counts are also elevated. Unlike HFRS, HPS does not present with renal involvement and hemorrhagic manifestations. (McCaughey and Hart 591). The mortality rate of HPS is 50% but patients who survive the acute phase enter the convalescent phase and recover without any long-term consequences of the disease (Muranyi et al. 3670).
The progression of HFRS can be categorized into five stages: febrile, hypotensive, oliguric, diuretic, and convalescent. The febrile stage is much like the prodromal phase in HPS but can also include abdominal pain, backache, and bradycardia. Photophobia, eruptions of the pharyngeal mucus membranes, a reddening of the face, intra-dermal hemorrhaging of the palate and conjunctival membranes, and blood in the urine has also been reported as this phase progresses. Urinalysis performed during this phase can show an increased level of proteins. The hypotensive phase can present with shock associated with the decrease in blood pressure. Blood tests during this phase can reveal decreased levels of platelets and an increase in the white blood cell count. Inflammation of the tubules and glomeruli of the kidney along with a buildup of IgA is marked in this phase. Hemorrhagic manifestations increase during the oliguric phase leading to increased renal involvement during the diuretic phase. The mortality rate of HFRS is 6-15% but patients who survive the acute phases enter the convalescent phase. Most recover without any long-term consequences of the disease, but rarely chronic renal failure and hypertension can persist (Muranyi et al. 3670). Although neither HPS nor HRFS cause visible cytopathic effects, severity of both diseases is related to the increased permeability of the infected endothelial cells (Muranyi et al. 3672). McCaughey and Hart propose that the initial viral attachment to cellular Beta-3 integrins may contribute to this because they help regulate vascular permeability and platelet function. Vascular dysfunction is the prominent abnormal cell function for both HPS and HFRS, however the host immune response rather than viral pathogenesis appears to play a major role (591, 592).
Both the innate and the adaptive immune systems are activated during an infection with hantavirus. The innate responses include the expression of interferons, activation of IFN-inducible genes, increased levels of antigen-presenting molecules, activation of the complement system, and the migration of natural killer cells into infected tissue. The adaptive immune responses include elevated titers of virus-specific IgA, IgE, and IgM. IgE activation of IL-1b and TNF-a as well as the release of pro-inflammatory cytokines by infected dendritic cells is thought to contribute to the increased permeability of infected endothelium. The viral clearance by the immune system is carried out mainly by the activity of the Cytotoxic CD8+ T cells (CTL) and a correlation exists between disease severity and CTL levels in the blood (Muranyi et al. 3673).
There are no antiviral drugs available for the treatment of hantavirus infections. Studies have been conducted on the guanosine-analog ribavirin because its incorporation into viral RNA causes high lethal mutation frequencies during the viral replication cycle. Studies are also being conducted on the use of interferons and IFN-inducible genes to interfere with the replication cycle of the virus. It is hoped that these studies, other novel studies being done on plant compounds and traditional Chinese medicines, or traditional research on the exact molecular mechanisms involved in hantavirus pathophysiology will one day provide effective treatment options (Muranyi et al. 3673). However, until an effective therapy is found, the main treatment continues to be supportive and focuses on the management of the bodyââ‚¬â„¢s fluid and electrolyte balance. Inotropic and vasopressor drugs may be used to maintain blood pressure and cardiac output. Patients in the acute phases are kept in intensive care units in hospitals where blood gas monitoring, dialysis, or mechanical ventilation can be provided if necessary. Heparin and platelets are administered to support normal coagulation if disseminated intravascular coagulation (DIC) occurs. In severe cases of HPS extracorporeal membrane oxygenation (ECMO) may be used until the immune system clears the virus and lung function recovers (McCaughey and Hart 594).
There is no hantavirus vaccine available worldwide, however there is a commercially available vaccine in Korea. Hantavax is a formalin-inactivated vaccine made from virus from a rodent brain. It has been shown to induce high titers of virus specific IgG antibodies in almost all of the test subjects after three vaccinations. However, the protection diminishes quickly as antibody levels drop within months. Research continues on inactivated, killed virus, plasmid-based, and recombinant DNA vaccines but it is unlikely that one will be developed in the near future. (Muranyi et al. 3675).
The most effective way of preventing infection with hantavirus is to minimize exposure to rodents and/or their excretions, including feces, urine, and saliva. All possible points of access into the home should be eliminated as well as removal of any open food sources in or around the home. Any occupation that performs work in areas where rodents may be present should have proper guidelines and procedures in place to limit exposure. All laboratory work done with hantaviruses should be conducted in biosafety III conditions following all safety protocols. Monitoring the prevalence of hantaviruses within the rodent populations can indicate when human cases are more likely to occur. Additionally, monitoring environmental conditions that favor increases in rodent populations can also help predict when human populations are at an increased risk of exposure, as was the case in the Four Corners outbreak in 1993 (McCaughey and Hart 594).
Hantaviruses are divided into two main groups, New World and Old World. Old World hantaviruses cause HFRS or Nephropathia epidemica (NE), a milder variant. HFRS affects 200,000 people a year with the majority of cases in Asia where the HTNV species has a mortality rate of 15%. New World hantaviruses cause approximately 300 cases of HPS in the Americas annually with a mortality rate of 50% (Muranyi et al. 3669). The CDC reports that there have been 534 cases of HPS in the US through December 1, 2009. The mortality rate for these cases is 36%. The mean age of those affected is 37 years and 63% of the cases were male. Thirty-one states reported cases, most of them in the west and three quarters in rural areas (http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/caseinfo.htm). After four cases of HPS involving children from different parts of the US occurred in 2009, the CDC advised physicians to consider HPS when they saw children that presented with unexplained respiratory conditions ("CDC: Consider Hantavirus pulmonary syndromeââ‚¬Â). Children are at an increased risk because they often play in areas that may expose them to rodents.
Several factors make hantavirus infections important emerging zoonotic diseases. Often the young and healthy are more vulnerable because they work and play in areas that put them in contact with rodents and/or their excretions. Since the hostââ‚¬â„¢s immune response directly relates to the severity of the disease, healthy individuals with strong immune systems often have more severe complications. This was the case in the Four Corners outbreak of HPS in the 1990s. HPS has a high mortality rate and currently there are no antiviral medications or vaccines to treat or prevent the disease. Hantaviruses, like all RNA viruses, are prone to mutations. It is possible that a mutation caused the Andes Sout strain to become transmissible via person-to-person contact in the outbreak in Argentina. The consequences of a virus capable of person-to-person transmission, a high mortality rate, and no known treatment entering a densely populated area are alarming. Understanding the molecular mechanisms involved in hantavirus pathophysiology and development of an effective treatment or vaccine is our best defense against future threats.