Attention to Hantavirus infections in the western world was first paid during the Korean war (1951-1953) when more than 3000 soldiers developed a disease characterised mainly by fever and renal failure. The disease, which became known as Korean hemorrhagic fever, had a fatality rate of approximately 10%. Not until 1976 was the etiologic agent of KHF was identified in field mice (Apodemus agrarius) and isolated in the laboratory. The virus was designated Hantaan virus after a river in Korea.

Soon thereafter, Finnish researchers showed a relationship between Hantaan virus and virus in lung tissue from bank voles (Clethrionomys glareolus) trapped close to locations where individuals had contracted nephropathia epidemica (NE). The clinical symptoms of NE are similar to Korean hemorrhagic fever, although haemorrhages are much more uncommon. The disease usually lasts for 7-10 days without sequel. The mortality of NE is much lower as compared to KHF, less than 0.2%. The causative agent of NE, Puumala virus, was isolated in the early eighties. Seoul and Dobrava viruses are two other hantaviruses that also cause similar diseases, commonly called hemorrhagic fever with renal syndrome (HFRS).

In 1993, a previously unknown human infectious disease was recognised in the USA. The infection mainly affected the lungs with a fatality rate of approximately 60%. This initiated an intense research activity, and after only a few months the causative agent was identified and partially characterised. It was shown to be a not previously recognised Hantavirus, later designated Sin Nombre virus. The disease was named Hantavirus pulmonary syndrome (HPS). The well-characterised hantaviruses to date associated with human disease are summarised in Table 1. Several additional Sin Nombre-like hantaviruses have recently been associated with HPS in the USA.

Table 1.

The structure of a Hantavirus is schematically described in Figure 1. The virus particle is approximately 120 nm and consists of four proteins: the nucleocapsid protein (N), the surface glycoproteins (G1 and G2) and the RNA polymerase. Both glycoproteins express regions that can be neutralised by antibodies and are believed to be involved in the binding to target cells. Any specific target cells or cell receptors are not known to date. The genome consists of three single-stranded RNA segments (S, M, L) of negative polarity.

Figure 1

Epidemiology

NE occurs in the Nordic countries (Finland, Sweden and Norway), western Russia and in Central Europe. Sweden reports approximately 200 cases, Finland 1.000 and Russia more than 10.000 cases of NE each year. Most cases of KHF are reported from China and eastern Russia. The total number of HFRS cases has been estimated to approximately 200.000 each year.

Only few cases of HPS have been reported since the first outbreak in 1993. In total, around 200 HPS cases have been diagnosed. No Hantavirus vaccines are available to date, although intense research programmes have been initiated, mainly on sub-component vaccines based on recombinant antigens.

All known hantaviruses seem to have one unique, species-specific, natural rodent reservoir (Table 1.) The rodents are chronically infected without any visible symptoms. Virus is spread to man via aerosolised rodent excreta. Man-to-man transfer of the viruses has not been reported.

The discovery of the highly lethal Sin Nombre Hantavirus intensified the Hantavirus research. During the recent years several additional unique hantaviruses have been recognised in "new" rodent species, both in the USA and in Europe. Since hantaviruses are extremely difficult to isolate in cell-culture, this research has been significantly facilitated by efficient genome sequencing directly from the infected rodent tissues. If the two new European members of the genus Hantavirus, Tula and Topografov viruses, cause any human disease remains to be investigated.

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Phylogenetic analysis

By the modern and efficient methods for genome sequence analysis, the genetic relationships between several hantaviruses have been determined (Figure 2., Hörling et al., 1996). Hantaan, Seoul and Dobrava viruses are found in the upper part of the phylogenetic tree. Another group comprises different American Sin Nombre-like viruses. Puumala virus strains from Sweden, Finland and Russia are found in the lower part of the tree. The methodology also gives an opportunity to interesting studies concerning the evolution of hantaviruses; e.g. on the spread of hantaviruses over different geographical regions and the correlation of the genetic relationships between the viruses and their natural rodent hosts.

Figure 2.

Diagnostics

Since hantaviruses are difficult to isolate in cell-culture, virus isolation is not suitable for patient diagnosis. Although highly sensitive PCR-methods have been developed during recent years, they are not of practical use in patient diagnosis. Only about 10% of the NE patients have detectable levels of viral RNA at the onset of the disease. Therefore, serology is of great importance for diagnosis of HFRS. The classical method for measurement of Hantavirus-specific antibodies is the immunofluorescence assay (IFA). However, there are several disadvantages with the method, e.g. difficulties in standardisation, subjectivity in the interpretation of results, and the handling of infectious virus for antigen preparation. More efficient ELISA methods, based on monoclonal antibodies and recombinant viral antigen, have been developed. IgM ELISA for detection of virus-specific IgM is the optimal method for serological diagnosis of acute Hantavirus infections.