They are enveloped viruses with a tripartite negative-sense RNA genome. The three genome segments are called L, M and S; they encode the viral transcriptase, envelope glycoproteins, and nucleocapsid protein, respectively.
The prototype hantavirus is Hantaan virus (HTN), which infects the Asian striped field mouse Apodemus agrarius (Lee, 1978, Yanagihara, 1987a). In the rodent host HTN causes a chronic infection that does not appear to result in disease. When the virus is transmitted from mice to humans, an acute disease known as hemorrhagic fever with renal syndrome (HFRS, Korean hemorrhagic fever) results. Similar syndromes, although generally less severe, are caused by the related Puumala virus (PUU), Seoul virus (SEO), and Belgrade (Dobrava, DOB) virus. Mortality rates for HTN and DOB HFRS are the highest among the hantavirus-associated diseases, at approximately 5-20%. It is estimated that more than 100,000 people in China contract HFRS annually (Yanagihara, 1987a). All of the hosts for viruses associated with HFRS are associated with rodent hosts indigenous to the Old World (table). SEO is somewhat exceptional in that the worldwide spread of its host rodent, Rattus norvegicus, has resulted in the worldwide spread of SEO.
HFRS is an acute febrile illness that was first recognized in the western world after a 1951 outbreak among U.S. troops stationed in Korea. Fever and myalgia (muscle pain) develops days or weeks after exposure to rodents. The disease progresses to hemorrhage (gastrointestinal, subconjunctival, etc) and hemodynamic instability, occasionally progressing to shock. There is acute renal failure, but the precise pathophysiologic lesion producing renal failure is uncertain. Mortality is usually from shock or hemorrhage.
The prototypic New World hantavirus is Prospect Hill virus (PHV) of the meadow vole Microtus pennsylvanicus. It has not been associated with human disease, but is widespread among voles in the United States and Canada (Lee, 1982; Yanagihara, 1987b). Serologic evidence for hantavirus infection in deer mice (Peromyscus maniculatus) has been recognized for several years (Tsai, 1985, Yanagihara, 1987b) but was generally ascribed to "spillover" of PHV from M. pennsylvanicus. Isolation attempts had been unsuccessful.
Despite extensive study, no arthropod vector has been implicated in the transmission of any hantavirus. The route by which the virus is transmitted to humans therefore is believed to be via aerosols of infected excreta of rodents (Zu, 1985; Tsai, 1987). Infected rodents appear to be persistently infected and viruric (have virus in their urine). HTN seroprevalence among mice in endemic areas, as assessed by seroreactivity to culture-adapted Hantaan virus, fluctuates in a biphasic manner: a small peak of seroprevalence in the spring season usually is followed by a decline over the summer months; then a higher peak occurs in the autumn. The incidence of HFRS among humans follows a similar trend, but the curve slightly trails the seroprevalence curve among A. agrarius populations. Those individuals whose occupations (eg, farmer) place them at greater exposure to dust or aerosols containing A. agrarius excreta are the most commonly affected.
Table 1. Hantaviruses and rodent hosts
The Four Corners hantavirus (FCV) was shown to be the etiologic agent for cases occurring in the western United States. P. maniculatus was implicated as the host for FCV in New Mexico, Colorado, and Arizona (CDC, 1993a; Nichol, 1993; Childs, 1994; Nerurkar, 1993; Nerurkar, 1994). Of the 79 cases of HPS known as of July 1, 1994, nearly all have been linked to FCV, and isolates (Sin Nombre virus; Convict Creek virus) were made from New Mexico and California deer mice (CDC, 1994a; Hjelle, 1994b; Schmaljohn, 1995). In most cases, that linkage was made possible through the use of reverse transcription-PCR (RT-PCR) analyses of the viral genetic material, using human autopsy tissue (Nichol, 1993) or peripheral blood mononuclear cells (Hjelle, 1994d) as template. For a few cases, RT-PCR studies were not conducted because (a) frozen, unfixed autopsy tissues were not available and immunohistochemical staining was used to reveal hantaviral antigenic material in the fixed lung tissue, or (b) the patient recovered and cleared the virus, and infection was documented retrospectively on clinical and serologic grounds (Jenison, 1994; CDC, 1994a; Zaki, 1993; Wilson, 1994). In two cases, the serologic response to distant hantavirus infections in New Mexico case-patients included antibodies to the FCV G1 glycoprotein, which appears to be distinctive for FCV or BCCV infection (Wilson, 1994; Jenison, 1994; Hjelle, 1994c; Jenison S and Hjelle B, unpublished). For a small, unknown number of western HPS case-patients, RT-PCR or serologic studies have not formally proven that FCV was the etiologic agent.
A few exceptional cases have greatly expanded the definition of potential agents of HPS. A man in Florida contracted HPS at a drug rehabilitation center. He recovered before the illness was recognized as HPS, and viral genetic material could not be amplified from his blood (CDC, 1994b). A novel hantavirus, BCCV, was later isolated from seropositive cotton rats (Sigmodon hispidus) trapped at the rehabilitation center, and persuasive evidence was presented that BCCV was responsible for the man's illness (CDC, 1994b; CDC, 1994c; Hjelle, 1994c). A young man succumbed to HPS after exposure in Rhode Island or New York in January, 1994. The etiologic agent proved to have 93% nucleocapsid protein sequence identity to a New Mexico FCV, but nucleotide sequence similarity was much lower (83%) (Hjelle, 1995b; CDC, 1994c). A patient from Monroe, Louisiana, died of HPS in 1993. A hantavirus M segment cDNA was amplified from autopsy lung tissue, and shown to be phylogenetically distinct from FCV (CDC, 1994b). In these 3 cases, and in at least one additional case (eastern Texas), HPS was apparently contracted outside of the range of P. maniculatus (CDC, 1994a; CDC, 1994c).
Centers for Disease Control and Prevention. 1993a. Outbreak of acute illness- Southwestern United States, 1993. Morbid. Mortal Weekly Rep 42:421-424.
Centers for Disease Control and Prevention. 1994a. Update: Hantavirus disease- United States, 1993. Morbid. Mortal Weekly Rep 42:612-614.
Centers for Disease Control and Prevention. 1994b. Newly identified hantavirus- Florida, 1994. Morbid. Mortal Weekly Rep 43:99, 105.
Centers for Disease Control and Prevention. 1994c. Hantavirus pulmonary syndrome - Northeastern United States, 1994. Morbid. Mortal Weekly Rep 43:549,555-556.
Centers for Disease Control and Prevention. 1994d. Laboratory management of agents associated with hantavirus pulmonary syndrome: interim biosafety guidelines. Morbid. Mortal. Weekly Rep. 43/RR- 7:1-7.
Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, Gage KL, Rollin P, Sarisky J, Enscore R, Peters CJ, Nichol ST. 1994. Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis 169:1271-80.
Chu YK, Lee HW, LeDuc JW, Schmaljohn CS, Dalrymple JM. 1994. Serological relationships among viruses in the Hantavirus genus, family Bunyaviridae. Virology 198: 196-204.
Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, Ksiazek TG, Rollin P, Nichol S, Umland E, Moolenaar RL, Reef SE , Nolte KB, Gallaher MM, Butler JC, Breiman RF, and the Hantavirus Study Group. 1994. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. N Engl J Med 330:949-955.
Elliott RM, Schmaljohn CS, Collett MS. 1991. Bunyavirus genome structure and gene expression. Curr Topi Microbiol Immunol 169:91-141.
Gligic A, Frusic M, Obradovic M, Stojanovic R, Hlaca D, Gibbs CJ Jr, Yanagihara R, Calisher CH, Gajdusek DC. 1989 Hemorrhagic fever with renal syndrome in Yugoslavia: antigenic characterization of hantaviruses isolated from Apodemus flavicollis and Clethrionomys glareolus. Am J Trop Med Hyg 41:109-115.
Gligic A, Dimkovic N, Xiao S-Y, Buckle GJ, Jovanovic D, Velimirovic D, Stojanovic R, Obradovic M, Diglisic G, Micic J, Asher DM, LeDuc JW, Yanagihara R, Gajdusek DC. 1992. Belgrade virus: a new hantavirus causing severe hemorrhagic fever with renal syndrome in Yugoslavia. J Infect Dis 166:113-120.
Hjelle B, Jenison S, Torrez-Martinez N, Yamada T, Nolte K, Zumwalt R, MacInnes K, Myers G. 1994a. A novel hantavirus associated with an outbreak of fatal respiratory disease in the southwestern United States: evolutionary relationships to known hantaviruses. J Virol 68:592- 6.
Hjelle B, Jenison S, Mertz G, Koster F, Foucar K. 1994b. Emergence of hantavirus disease in the southwestern United States. Western J Med (in press).
Hjelle B, Chavez-Giles F, Torrez-Martinez N, Yamada T, Sarisky J, Ascher M, Jenison S. 1994c. The dominant glycoprotein epitope of Four Corners hantavirus is conserved across a wide geographic area. J Gen Virol 75:2881-8.
Hjelle B, Spiropoulou CF, Torrez-Martinez N, Morzunov S, Peters CJ, Nichol ST. 1994d Detection of Muerto Canyon virus RNA in peripheral blood mononuclear cells from patients with hantavirus pulmonary syndrome J Infect Dis 170:1013-7.
Hjelle B, Chavez-Giles F, Torrez-Martinez N, Yates T, Sarisky J, Webb J, Ascher M. 1994e. Genetic identification of a novel hantavirus of the harvest mouse Reithrodontomys megalotis. J Virol 68:6751-4.
Hjelle B. 1995a. Outbreak of hantavirus pulmonary syndrome in the United States: detection of Four Corners virus by PCR. Chapter in Y. Becker and G. Darai (eds). PCR: Protocols for Diagnosis of Human and Animal Virus Diseases, Frontiers in Virology, New York and Heidelberg (in press).
Jenison S, Yamada T, Morris C, Anderson B, Torrez-Martinez N, Keller N, Hjelle B. 1994. Characterization of human antibody responses to Four Corners hantavirus infections among patients with hantavirus pulmonary syndrome. J Virol 68:3000-6.
Lee, HW, Lee P-W, Johnson KM. 1978. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 137:298-308.
Lee P-W, Amyx HL, Gajdusek DC, Yanagihara RT, Goldgaber D, Gibbs, CJ Jr. 1982. New haemorrhagic fever with renal syndrome-related virus in indigenous wild rodents in United States. Lancet 2:1405.
Lee HW, Baek LJ, Johnson KM. 1983. Isolation of Hantaan virus, the etiologic agent of Korean hemorrhagic fever from wild urban rats. J Infect Dis 146:638-644.
Lee P-W, Gibbs CJ Jr, Gajdusek DC, Yanagihara R. 1985. Serotypic classification of hantaviruses by indirect immunofluorescent antibody and plaque reduction neutralization tests. J Clin Microbiol 22:940-944.
Nerurkar VR, Song K-J, Gajdusek DC, Yanagihara R. 1993. Genetically distinct hantavirus in deer mice. Lancet 342:1059.
Nerurkar VR, Song K-J, Song J-W, Nagle JW, Hjelle B, Jenison S, Yanagihara R. 1994. Genetic evidence for a hantavirus enzootic in deer mice (Peromyscus maniculatus) a decade before the recognition of hantaviral pulmonary syndrome. Virology (in press).
Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldmann H, Sanchez A, Childs J, Zaki S, Peters CJ. 1993. Genetic identification of a novel hantavirus associated with an outbreak of acute respiratory illness in the southwestern United States. Science 262:914-7.
Schmaljohn AL, Li D, Negley DL, Bressler DS, Turell MJ, Korch GW, Ascher MS, Schmaljohn CS. 1995. Isolation and initial characterization of a newfound hantavirus from California. (submitted).
Spiropoulou CF, Morzunov S, Feldmann H, Sanchez A, Peters CJ, Nichol ST. 1994. Genome structure and variability of a virus causing hantavirus pulmonary syndrome. Virology 200:715-23.
Tsai TF, Bauer SP, Sasso DR, Whitfield SG, McCormick JB, Caraway TC, McFarland L, Bradford H, Kurata T. Serological and virological evidence of a Hantaan virus-related enzootic in the United States. J Infect Dis 1985;152:126-136.
Tsai TF. 1987. Hemorrhagic fever with renal syndrome: mode of transmission to humans. Lab Anim Sci 37:428-30.
Wilson C, Hjelle B, Jenison S. 1994. A probable case of hantavirus pulmonary syndrome that occurred in New Mexico in 1975. Ann Int Med 120:813.
Xiao S-Y, LeDuc JW, Chu Y-K, Schmaljohn CS. 1994. Phylogenetic analysis of virus isolates of the genus hantavirus, family bunyaviridae. Virology 198:205-217.
Yanagihara R, Daum CA, Lee P-W, Baek LJ, Amyx HL, Gajdusek C, Gibbs CJ Jr. 1987a. Serologic survey of Prospect Hill virus infection in indigenous wild rodents in the USA. Trans Royal Society Trop Med Hyg 81:42-45.
Yanagihara R, Gajdusek DC. 1987b. Hemorrhagic fever with renal syndrome: global epidemiology and ecology of hantavirus infections. In L.M. de la Maza and E.M. Peterson (eds), Medical Virology VI; Elsevier Science Publishers, Washington, DC.
Yanagihara, R. 1990. Hantavirus infection in the United States: epizootiology and epidemiology. Rev Infect Dis 12:449-57.
Zaki SR, Greer PW, Coffield LB, Nolte KB, Zumwalt RE, Umland ET, Feddersen RM, Foucar K, Rua SJ, Rollin P, Ksiazek T, Nichol S, Peters CJ. 1994. Outbreak of hantavirus- associated illness in the United States: immunohistochemical localization of viral nucleoproteins to endothelial cells in human tissues. Lab Invest 70:129A (abstract).
Zu Z-Y, Guo C-S, Wu Y-L, Zhang X-W, Liu K. 1985. Epidemiological studies of hemorrhagic fever with renal syndrome: analysis of risk factors and mode of transmission. J Infect Dis 152:137-43.