In May 1993, a clinician reported a cluster of cases presenting with nonspecific illness, fever, headache, and cough that rapidly progressed to respiratory distress. The patients were young, previously healthy, and lived in rural areas in the four-corners region bordering Arizona, Colorado, New Mexico, and Utah. By early June 1993, 24 cases had been reported with a mortality rate approximately 75%.11,12 Patient blood and autopsy tissues were sent to the Centers for Disease Control (CDC) for investigation. Diagnostic assays failed to identify known causes of respiratory illness; however, patient samples cross-reactived with antibodies to four different hantaviruses. Using hantavirus sera, immunohistochemistry detected hantavirus antigen in autopsy tissue from the lung and other involved organs.13 Hantaviruses are RNA viruses with a genome in three segments and a member of the family Bunyaviridae. Previous outbreaks of hantaviruses involved patients with renal disease leading to hemorrhagic complications, not respiratory distress. Hantaviruses are classified into four antigenic groups, and each strain of hantavirus is tightly associated with a specific rodent host. Although hantaviruses have a worldwide distribution, the dependence on a particular species of rodent host restricts the geographical range. Hantaan (HTN) is associated with the field mouse in Korea, China, and eastern Russia and causes hemorrhagic fever with renal syndrome (HFRS). Seoul (SEO) causes moderate disease in Korea and China and is associated with urbanized rats. A milder form of HFRS is caused by the serogroup Puumula (PUU) in Scandinavia and Europe and is transmitted by the bank vole. At the time of the four-corners outbreak, the only North American hantavirus identified was Prospect Hill (PH), which was detected in two rodent isolates of meadow voles and not associated with any human illness. Patient samples from the U.S. four-corners region cross-reacted with han-tavirus antigen and allowed epidemiologists to expand their assays to include RT-PCR and narrow the search for the host to local rodents. The virus was unable to be cultured from patient samples; therefore, molecular identification was crucial for identification. Partial sequences were available for HTN, SEO, PUU, and PH in a database and used to design PCR primers based on conserved areas of the virus glycoprotein. Nucleic acid was extracted from autopsy tissue, and a PCR product was detected in two cases using primer pairs based on PUU and PH. The PCR product was sequenced, revealing a 70% sequence similarity between the new virus and PH and PUU.14 New primers were designed and could detect products in all current cases. The sequence of the new virus was identified, and the nucleocapsid protein was expressed in bac teria and purified and used as a recombinant antigen in other serological assays.15 The new virus was eventually named Sin Nombre virus (SNV).
Rodents were trapped in areas in and surrounding patient houses. The predominant species was the field mouse, Peromyscus maniculitis, and approximately 30% had anti-hantavirus antibodies detected in an IgG ELISA. PCR revealed that 82% had detectable virus in the blood, indicating high viremia even in the presence of circulating antibodies. Sequences from rodent and human cases isolated in the four states were aligned, and identical nucleotide substitutions were present in the rodent and human cases from the same location, indicating that transmission occurred from the field mouse to the human cases.14 Transmission occurred by inhalation of aerosolized rodent urine. Ecol-ogists reported an increase in the population of field mice during that year due to a surplus food supply. The arid conditions of the southwest and the close proximity of the mice and the patients also contributed to transmission. In this outbreak, there were no reports of human-human transmission.16
The discovery of SNV led to a heightened awareness and search for other American hantaviruses. Field investigations and retrospective serological studies identified additional hantaviruses in North America.17 The North American viruses show an 80%-95% similarity, but are always found only in their specific rodent species.18 The detection of the new hantaviruses is enhanced by the use of diagnostic reagents developed in this outbreak and refined as new viruses are identified. Additional cases have also been detected in South America. In 1995, Andes virus was isolated in Argentina, the only documented case of human-human transmission.19 Hantavirus outbreaks have also been identified in Chile, Paraguay, Bolivia, and Brazil, causing both respiratory illness and some renal hemorrhagic disease. South American cases show higher virus titers and also persistently infect a distinct rodent species as a natural reservoir.
After the SNV outbreak, efforts increased to study the relationships between hantaviruses and the rodent hosts worldwide. Phylogenetic analysis of rodent and human virus sequences has shown a close evolutionary relationship, and hantaviruses are often used as models of coevolution. A particular genotype of hantavirus persistently infects one species of rodent even though other rodent hosts may be present in the same environment. This remarkable coexistence has been mapped through changing landscapes. As a rodent species radiates farther away into another habitat, it may evolve into a separate, but genetically similar, species. The hitchhiker hantavirus also evolves with the rodent host, becoming genetically distinct from viruses associated with the ancestral species. This ancient relationship has been mapped using phylogenetic trees, which display common ancestral species as clusters that diverge and separate with geographical and genetic distance. The topology of the rodent tree can be compared and reveals similar patterns with topology of the associated hantaviruses.20 Phylogenies have been performed on rodent family, subfamily, genus, and species using mitochondrial DNA. Phylogenetic trees of han-taviruses reveal a similar branching pattern to the rodent tree. Viruses that infect the same subfamily of rodents form identical clades, and closely related hantaviruses are grouped in the same tree pattern as their rodent reservoirs. Although rare, there have been instances of transmission of one virus to another rodent species. This provides another example of molecular evolution where virus segments can mix in the host and form reassorted viruses containing combinations of different virus segments. This can contribute to genetic diversity. Reassortment of the segmented genome has been found in nature and in mixed virus infections in tissue culture, but only between very closely related viruses.21 Phylogenetic analysis performed on more than one virus segment tests for the chance of reassortment. Even in geographical locations where different rodent species may overlap, virus-host switching and reassortment are very rare events. Each hantavirus is associated with a primary rodent host, and usually a particular rodent species will be the primary reservoir of a single hantavirus. The tight correlation of virus and rodent host in the phylogenetic trees supports the concept of coevolution between virus and host. All subfamilies of the family Muridae have a hantavirus-rodent relationship. Fossil records estimate the rodent families Muridae to have split into the current subfamilies during the Miocene period, indicating that hantaviruses have been associated with their rodent hosts for 30 million years, an association that began before the division of the rodent family.22 The coevolutionary relationship and worldwide distribution of hantavirus illustrates that the 1993 SNV outbreak was not due to the emergence of a new virus or virus with an increased virulence, but simply the detection of an ancient virus.
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