[Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997]
Synopses
Hantaviruses: A Global Disease Problem
Connie Schmaljohn* and Brian Hjelle
*United States Army Medical Research Institute of Infectious Diseases, Fort
Detrick, Frederick, Maryland, USA; and University of New Mexico,
Albuquerque, New Mexico, USA
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      Hantaviruses are carried by numerous rodent species throughout
      the world. In 1993, a previously unknown group of hantaviruses
      emerged in the United States as the cause of an acute
      respiratory disease now termed hantavirus pulmonary syndrome
      (HPS). Before then, hantaviruses were known as the etiologic
      agents of hemorrhagic fever with renal syndrome, a disease that
      occurs almost entirely in the Eastern Hemisphere. Since the
      discovery of the HPS-causing hantaviruses, intense
      investigation of the ecology and epidemiology of hantaviruses
      has led to the discovery of many other novel hantaviruses.
      Their ubiquity and potential for causing severe human illness
      make these viruses an important public health concern; we
      reviewed the distribution, ecology, disease potential, and
      genetic spectrum.
The genus Hantavirus, family Bunyaviridae, comprises at least 14 viruses,
including those that cause hemorrhagic fever with renal syndrome (HFRS) and
hantavirus pulmonary syndrome (HPS) (Table 1). Several tentative members of
the genus are known, and others will surely emerge as their natural ecology
is further explored. Hantaviruses are primarily rodent-borne, although
other animal species harboring hantaviruses have been reported. Unlike all
other viruses in the family, hantaviruses are not transmitted by arthropod
vectors but (most frequently) from inhalation of virus-contaminated
aerosols of rodent excreta (1). Human-to-human transmission of hantaviruses
has not been documented, except as noted below.
 Table 1. Members of the genus Hantavirus, family Bunyaviridae
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     Species      Disease    Principal     Distribution   Distribution of
                             Reservoir       of Virus        Reservoir
 --------------------------------------------------------------------------
 Hantaan (HTN)    HFRS(a) Apodemus         China,       C Europe south to
                          agrarius         Russia,      Thrace, Caucasus,
                          (striped field   Korea        & Tien Shan Mtns;
                          mouse)                        Amur River through
                                                        Korea to E Xizang
                                                        & E Yunnan, W
                                                        Sichuan, Fujiau, &
                                                        Taiwan(China)
 Dobrava-Belgrade HFRS    Apodemus         Balkans      England & Wales,
 (DOB)                    flavicollis                   from NW Spain,
                          (yellow-neck                  France, S
                          mouse)                        Scandinavia
                                                        through European
                                                        Russia to Urals, S
                                                        Italy, the
                                                        Balkans, Syria,
                                                        Lebanon, & Israel
 Seoul (SEO)      HFRS    Rattus           Worldwide    Worldwide
                          norvegicus
                          (Norway rat)
 Puumala (PUU)    HFRS    Clethrionomys    Europe,      W Palearctic from
                          glareolus        Russia,      France and
                          (bank vole)      Scandinavia  Scandinavia to
                                                        Lake Baikai, south
                                                        to N Spain, N
                                                        Italy, Balkans,W
                                                        Turkey, N
                                                        Kazakhstan, Altai
                                                        & Sayan Mtns;
                                                        Britain & SW
                                                        Ireland
 Thailand (THAI)  nd(b)   Bandicota        Thailand     Sri Lanka,
                          indica                        peninsular India
                          (bandicoot rat)               to Nepal, Burma,
                                                        NE India, S China,
                                                        Laos, Taiwan,
                                                        Thailand, Vietnam
 Prospect Hill    nd      Microtus         U.S., Canada C Alaska to
 (PH)                     pennsylvanicus                Labrador,
                          (meadow vole)                 including
                                                        Newfoundland &
                                                        Prince Edward
                                                        Island, Canada;
                                                        Rocky Mountains to
                                                        N New Mexico, in
                                                        Great Plains to N
                                                        Kansas, & in
                                                        Appalachians to N
                                                        Georgia, U.S.
 Khabarovsk (KHB) nd      Microtus fortis  Russia       Transbaikalia Amur
                          (reed vole)                   region; E China
 Thottapalayam    nd      Suncus murinus   India        Afghanistan,
 (TPM)                    (musk shrew)                  Pakistan, India,
                                                        Sri Lanka, Nepal,
                                                        Bhutan, Burma,
                                                        China, Taiwan,
                                                        Japan, Indomalayan
                                                        Region
 Tula (TUL)       nd      Microtus         Europe       Throughout Europe
                          arvalis                       to Black Sea & NE
                          (European                     to Kirov region,
                          common                        Russia
                          vole)
 Sin Nombre (SN)  HPS(c)  Peromyscus       U.S.,        Alaska Panhandle
                          maniculatus      Canada,      across N Mexico
                          (deer mouse)                  Canada, south
                                                        through most of
                                                        continental U.S.,
                                                        excluding SE & E
                                                        seaboard, to
                                                        southernmost Baja
                                                        California Sur and
                                                        to NC Oaxaca,
                                                        Mexico
 New York (NY)    HPS     Peromyscus       U.S.         C and E U.S. to S
                          leucopus                      Alberta & S
                          (white-footed                 Ontario, Quebec &
                          mouse)                        Nova Scotia,
                                                        Canada; to N
                                                        Durango & along
                                                        Caribbean coast to
                                                        Isthmus of
                                                        Tehuantepec &
                                                        Yucatan Peninsula,
                                                        Mexico
 Black Creek      HPS     Sigmodon         U.S.         SE U.S., from S
 Canal                    hispidus                      Nebraska to C
 (BCC)                    (cotton rat)                  Virginia south to
                                                        SE Arizona &
                                                        peninsular
                                                        Florida; interior
                                                        & E Mexico through
                                                        Middle America to
                                                        C Panama; in South
                                                        Amer ica to N
                                                        Colombia & N
                                                        Venezuela
 El Moro Canyon   nd      Reithrodontomys  U.S., Mexico British Columbia &
 (ELMC)(d)                                              SE Alberta,
                          megalotis                     Canada; W and NC
                          (Western                      U.S., S to N Baja
                          harvest mouse)                California &
                                                        interior Mexico to
                                                        central Oaxaca
 Bayou (BAY)(d)   HPS     Oryzomys         U.S.         SE Kansas to E
                          palustris                     Texas, eastward to
                          (rice rat)                    S New Jersey &
                                                        peninsular Florida
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 Probable species:(e)
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 Topografov (TOP) nd      Lemmus           Siberia      Palearctic, from
                          sibiricus                     White Sea, W
                          (Siberian                     Russia, to
                          lemming)                      Chukotski
                                                        Peninsula, NE
                                                        Siberia, &
                                                        Kamchatka;
                                                        Nearctic, from W
                                                        Alaska E to Baffin
                                                        Island & Hudson
                                                        Bay, S Rocky Mtns
                                                        to C B.C., Canada
 Andes (AND)(d)   HPS     Oligoryzomys     Argentina    NC to S Andes,
                          longicaudatus(f)              approximately to
                                                        50 deg S latitude,
                          (long-tailed                  in Chile &
                          pygmy                         Argentina
                          rice rat)
 To be named(d)   HPS     Calomys laucha   Paraguay     N Argentina &
                          vesper mouse                  Uruguay, SE
                                                        Bolivia, W
                                                        Paraguay, and WC
                                                        Brazil
 Isla Vista       nd      Microtus         U.S.         Pacific coast,
 (ISLA)(d)                californicus                  from SW Oregon
                          (California                   through
                          vole)                         California, U.S.,
                                                        to N Baja
                                                        California, Mexico
 Bloodland Lake   nd      Microtus         U.S.         N & C Great
 (BLL)(d)                 ochrogaster                   Plains, EC Alberta
                          (prairie vole)                to S Manitoba,
                                                        Canada, S to N
                                                        Oklahoma &
                                                        Arkansas, E to C
                                                        Tennessee & W West
                                                        Virginia, U.S.;
                                                        relic populations
                                                        elsewhere in U.S.
                                                        & Mexico
 Muleshoe         nd      Sigmodon         U.S.         See Black Creek
 (MUL)(d)                 hipidus                       Canal
                          (cotton rat)
 Rio Segundo      nd      Reithrodontomys  Costa Rica   S Tamaulipas & WC
 (RIOS)(d)                                              Michoacan, Mexico,
                          mexicanus                     S through Middle
                          (Mexican                      American highlands
                          harvest mouse)                to W Panama; Andes
                                                        of W Colombia & N
                                                        Ecuador
 Rio Mamore       nd      Oligoryzomys     Bolivia      C Brazil south of
 (RIOM)(d)                microtis                      Rios Solimoes-
                          (small-eared                  Amazon &
                          pygmy                         contiguous low
                          rice rat)                     lands of Peru,
                                                        Bolivia, Paraguay,
                                                        & Argentina.
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 (a)HFRS, hemorrhagic fever with renal syndrome
 (b)nd, none documented
 (c)HPS, hantavirus pulmonary syndrome
 (d) not yet isolated in cell culture
 (e) viruses for which incomplete characterization is available, but for
 which there is clear evidence indicating that they are unique
 (f) suspected host, but not confirmed
 Adapted from (57,72) and from (9,13,23,38,42,43,50-71)
The recognition of a previously unknown group of hantaviruses as the cause
of HPS in 1993 is an example of virus emergence due to environmental
factors favoring of the natural reservoir; a larger reservoir increases
opportunities for human infection. We reviewed the global distribution of
hantaviruses, their potential to cause disease, and their relationships to
each other and to their rodent hosts.
History of HFRS and HPS
"Hemorrhagic fever with renal syndrome" denotes a group of clinically
similar illnesses that occur throughout the Eurasian landmass and adjoining
areas (2,3). HFRS includes diseases previously known as Korean hemorrhagic
fever, epidemic hemorrhagic fever, and nephropathia epidemica (4). Although
these diseases were recognized in Asia perhaps for centuries, HFRS first
came to the attention of western physicians when approximately 3,200 cases
occurred from 1951 to 1954 among United Nations forces in Korea (2,5).
Other outbreaks of what is believed to have been HFRS were reported in
Russia in 1913 and 1932, among Japanese troops in Manchuria in 1932 (2,6),
and in Sweden in 1934 (7,8). In the early 1940s, a viral etiology for HFRS
was suggested by Russian and Japanese investigators who injected persons
with filtered urine or serum from patients with naturally acquired disease
(2). These studies also provided the first clues to the natural reservoir
of hantaviruses: the Japanese investigators claimed to produce disease in
humans by injecting bacteria-free filtrates of tissues from Apodemus
agrarius or mites that fed on the Apodemus mice. Mite transmission was
never conclusively demonstrated by other investigators, and it was not
until 1978 that a rodent reservoir for HFRS-causing viruses was confirmed
by investigators who demonstrated that patient sera reacted with antigen in
lung sections of wild-caught Apodemus agrarius and that the virus could be
passed from rodent to rodent (9). The successful propagation of Hantaan
(HTN) virus in cell culture in 1981 provided the first opportunity to study
this pathogen systematically (10). The history of HFRS has been explored
(2,11,12).
HPS was first described in 1993 when a cluster of cases of adult fatal
respiratory distress of unknown origin occurred in the Four Corners region
of the United States (New Mexico, Arizona, Colorado, and Utah). The
unexpected finding that sera from patients reacted with hantaviral antigens
was quickly followed by the genetic identification of a novel hantavirus in
patients' tissues and in rodents trapped near patients' homes (13-15).
Prevalence and Clinical Course
Approximately 150,000 to 200,000 cases of HFRS involving hospitalization
are reported each year throughout the world, with more than half in China
(16). Russia and Korea also report hundreds to thousands of HFRS cases each
year. Most remaining cases (hundreds per year) are found in Japan, Finland,
Sweden, Bulgaria, Greece, Hungary, France, and the Balkan countries
formerly constituting Yugoslavia (16). Depending in part on which
hantavirus is responsible for the illness, HFRS can appear as a mild,
moderate, or severe disease (Table 2). Death rates range from less than
0.1% for HFRS caused by Puumala (PUU) virus to approximately 5% to 10% for
HFRS caused by HTN virus (16). The clinical course of severe HFRS involves
five overlapping stages: febrile, hypotensive, oliguric, diuretic, and
convalescent; it is not uncommon, however, for one or more of these stages
to be inapparent or absent. The onset of the disease is usually sudden with
intense headache, backache, fever, and chills. Hemorrhage, if it occurs, is
manifested during the febrile phase as a flushing of the face or injection
of the conjunctiva and mucous membranes. A petechial rash may also appear,
commonly on the palate and axillary skin folds. Sudden and extreme
albuminuria, around day 4, is characteristic of severe HFRS. As the febrile
stage ends, hypotension can abruptly develop and last for hours or days,
during which nausea and vomiting are common. One-third of deaths occur
during this phase because of vascular leakage and acute shock. Almost half
of all deaths occur during the subsequent (oliguric) phase because of
hypervolemia. Patients who survive and progress to the diuretic phase show
improved renal function but may still die of shock or pulmonary
complications. The final (convalescent) phase can last weeks to months
before recovery is complete (3,5,12).
 Table 2. Distinguishing clinical characteristics for HFRS and HPS
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           Disease             Pathogens  Distinguishing Characteristics*
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 HFRS (moderate-severe)      HTN, SEO,    hemorrhage +++
 Death rate                  DOB          azotemia/
 1%-15%                                   proteinuria +++/++++
                                          pulmonary capillary leak +/++
                                          myositis +/+++
                                          conjunctival injection ++/++++
                                          eye pain/myopia ++/++++
 HFRS (mild)                 PUU          hemorrhage +
 Death rate <1%                           azotemia/
                                          proteinuria +/++++
                                          pulmonary capillary leak -/+
                                          myositis +
                                          conjunctival injection +
                                          eye pain/myopia ++/++++
 HPS (prototype)             SN, NY       hemorrhage +
 Death rate >40%                          zotemia/
                                          proteinuria +
                                          pulmonary capillary leak ++++
                                          myositis -
                                          conjunctival injection -/+
                                          eye pain/myopia -
 HPS (renal                  BAY, BCC,    hemorrhage +
 variant)                    Andes        azotemia/
 Death rate>40%                           proteinuria ++/+++
                                          pulmonary capillary leak
                                          +++/++++
                                          myositis ++/++++
                                          conjunctival injection -/++
                                          eye pain/myopia -
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 *Minimum/maximum occurrence of the characteristic: - rarely reported;
 + infrequent or mild manifestation; ++, +++, ++++ more frequent and severe
 manifestation.
More than 250 cases of HPS have been reported throughout North and South
America. Although the disease has many features (e.g., a febrile prodrome,
thrombocytopenia, and leukocytosis) in common with HFRS (Table 2), in HPS
capillary leakage is localized exclusively in the lungs, rather than in the
retroperitoneal space, and the kidneys are largely unaffected. Most of the
174 cases of HPS in the United States and Canada have been caused by Sin
Nombre (SN) virus. In HPS, death occurs from shock and cardiac
complications, even with adequate tissue oxygenation. Cases of HPS in the
southeastern United States, as well as many in South America, are caused by
a newly recognized clade (a group that shares a common ancestor) of viruses
that includes Bayou (BAY), Black Creek Canal (BCC), and Andes viruses. As
with HFRS, clinical differences can be observed among patients with HPS
caused by different hantaviruses. For example, although HPS due to SN virus
infection can sometimes be associated with renal insufficiency after
prolonged hypoperfusion, renal impairment is only rarely observed early in
disease, and chemical evidence of skeletal muscle inflammation (increased
serum levels of the muscle enzyme creatine kinase) is rare (17). In
contrast, both renal insufficiency and elevated creatine kinase levels are
observed at much higher frequency, although not universally, with Andes,
BAY, and BCC virus infections (18-20; J. Davis, J. Cortes, and C. Barclay,
pers. comm.). In an outbreak of HPS recently described in Paraguay, a novel
hantavirus, carried by Calomys laucha, was identified as the etiologic
agent (21). The relationship of this virus to other HPS-causing
hantaviruses remains to be established.
Ecology and Epidemiology
Hantavirus infection is apparently not deleterious to its rodent reservoir
host and is associated with a brisk antibody response against the virion
envelope and core proteins and chronic, probably lifelong infection. In
natural populations, most infections occur through age-dependent horizontal
route(s). The highest antibody prevalence is observed in large (mature)
animals. A striking male predilection for hantavirus infection is observed
in some rodent species such as harvest mice and deer mice, but not in urban
rats (Rattus norvegicus) (22-24). Horizontal transmission among cage-mates
was experimentally demonstrated (25), but vertical transmission from dam to
pup is negligible or absent both in wild and experimental settings
(22,24,25).
Outbreaks of hantaviral disease have been associated with changes in rodent
population densities, which may vary greatly across time, both seasonally
and from year to year. Cycles respond to such extrinsic factors as
interspecific competition, climatic changes, and predation. Spring and
summer outbreaks of HFRS in agricultural settings in Asia and Europe are
linked to human contact with field rodents through the planting and
harvesting of crops (16,26). PUU outbreaks in Scandinavia and the HPS
outbreak in the Four Corners region of the United States were associated
with natural rodent population increases, followed by invasion of buildings
by rodents (27,28). The ecologic events that led to 1994 and 1996 outbreaks
of Andes virus-HPS in Patagonia, a region in southern South America, are
being investigated. Human interventions, such as the introduction of Old
World plant species (e.g., rosas mosquetas and Scottish brougham) to
Patagonia, with associated alteration in rodent population dynamics, have
been suggested as possible factors. Recent fires and a mild winter in
Argentina's Rio Negro and Chubut Provinces may also have had a positive
effect on the carrier rodent, the colilargo, Oligoryzomys longicaudatus (M.
Christie and O. Pearson, pers. comm.).
Although the aerosol route of infection is undoubtedly the most common
means of transmission among rodents and to humans, virus transmission by
bite may occur among certain rodents (29) and may also occasionally result
in human infection (30) (often inside a closed space, such as a
rodent-infested grain silo, garage, or outbuilding used for food storage).
Epidemiologic investigations have linked virus exposure to such activities
as heavy farm work, threshing, sleeping on the ground, and military
exercises. Indoor exposure was linked to invasion of homes by field rodents
during cold weather or to nesting of rodents in or near dwellings (16,31).
Genetic sequencing of rodent- and patient-associated viruses has been used
to pinpoint the precise locations of human infections, which has supported
the role of indoor exposure in hantavirus transmission (32,33). Many
hantavirus infections have occurred in persons of lower socioeconomic
status because poorer housing conditions and agricultural activities favor
closer contact between humans and rodents. However, suburbanization,
wilderness camping, and other outdoor recreational activities have spread
infection to persons of middle and upper incomes.
Nosocomial transmission of hantaviruses has not been documented until very
recently (34) and must be regarded as rare. However, viruses have been
isolated from blood and urine of HFRS patients, so exposure to bodily
fluids of infected persons could result in secondary transmission. Only
rarely have multiple North American HPS cases been associated with
particular households or buildings. During recent outbreaks of HPS in South
America, however, clustering of cases in households and among personal
contacts appeared to be more common (M. Christie, pers. comm.). During a
recent outbreak of Andes-virus-associated HPS in Patagonia, a Buenos Aires
physician apparently contracted the infection after minimal exposure to
infected patient blood (34; D.A. Pirola, pers. comm.). An adolescent
patient in Buenos Aires apparently contracted hantavirus infection from her
parents, who were infected in Patagonia. This unprecedented observation of
apparent person-to-person spread of a hantavirus clearly requires
laboratory confirmation, especially by careful comparative analysis of the
viral sequences (32,33).
Hantaviruses have also caused several laboratory-associated outbreaks of
HFRS. Laboratory-acquired infections were traced to persistently infected
rats obtained from breeders (35-37), to wild-caught, naturally infected
rodents (38-40), or to experimentally infected rodents (39). No illnesses
due to laboratory infections have been reported among workers using
cell-culture adapted viruses, although asymptomatic seroconversions have
been documented (40).
Hantavirus Distribution and Disease-causing Potential
The worldwide distribution of rodents known to harbor hantaviruses (Table
1) suggests great disease-causing potential. Each hantavirus appears to
have a single predominant natural reservoir. With rare exception, the
phylogenetic interrelationships among the viruses and those of their
predominant host show remarkable concordance (Figure; 41). These
observations suggest that hantaviruses do not adapt readily to new hosts
and that they are closely adapted for success in their host, possibly
because of thousands of years of coexistence. As many as three hantaviruses
can be found in a particular geographic site, each circulating in its own
rodent reservoir, with no apparent evolutionary influence on one another
(42).
[Figure 1] [Figures not available in ASCII version]
Figure. Phylogeny of hantaviruses and their relationships to natural
reservoirs. The trees were constructed by comparing the complete coding
regions of the S segments of hantaviruses or of 330 nucleotides
corresponding to those of the M segment of Hantaan virus (strain 76118)
from nucleotides 1987 to 2315. Abrreviations for viruses are as in Table
1. For each analysis, a single most parsimonious tree was derived by using
PAUP 3.1.1 software. For the S segment tree, boostrap values resulting
from 100 replications were all greater than 87% except for the branch
leading to BCC (78%) and the branch leading to DOB (52%). The next most
common placing of DOB was on a branch with HTN.
All known hantaviruses, except Thotta-palayam (TPM) virus, have been
isolated or detected in murid rodents. Because only one isolate of TPM
virus was made from a shrew (Order Insectivora), it is not clear if Suncus
is the true primary reservoir or an example of a "spillover" host, i.e., a
secondary host infected through contact with the primary host. Spillover is
common in sympatric murid rodents, including those identified as the
predominant carrier of another hantavirus; thus, the opportunity for
genetic exchange among hantaviruses is present in nature. Spillover hosts
are believed to have little or no impact on hantaviral distribution or
associated disease. However, rodents other than the primary reservoirs can
play an important carrier role. For example, Microtus rossiaemeri-dionalis
may play a role in maintenance of Tula virus in some settings (43), and
Peromyscus leucopus and Peromyscus boylii can be important reservoirs for
SN virus in the western United States (T. Yates and B. Hjelle, unpub.
data). Apparent spillover may also be the result of laboratory errors such
as polymerase chain reaction (PCR) contamination or misidentification of
rodent species. However, spillover is probably under-appreciated in many
studies that rely on reverse transcriptase PCR for identifying specific
viruses because many primer pairs may not detect an unexpected spillover
virus. In either case, because mistaken identities and cell culture
contaminations with other hantaviruses have occasionally been reported,
investigators should verify unusual findings to prevent further confusion.
Antigenic and Genetic Diversity among Hantaviruses
Hantaviruses have been characterized by a combination of antigenic and
genetic methods. For viruses propagated in cell culture, the
plaque-reduction neutralization test is the most sensitive serologic assay
for differentiation (44,45); nine hantaviruses have been defined by this
test: HTN, Seoul (SEO), PUU, Prospect Hill, Dobrava-Belgrade (DOB),
Thailand, TPM, SN, and BCC viruses (44-48). Genetic relationships among
hantaviruses are mirrored in their antigenic properties. A direct
correlation between genetic and antigenic relationships is difficult;
however, it can be assumed that the plaque-reduction neutralization test
measures differences in the M segment gene products, i.e., the G1 and G2
envelope glycoproteins. Comparing the deduced G1 and G2 amino acid
sequences, therefore, may provide clues to the antigenic as well as genetic
diversity among hantaviruses.
Of characterized hantavirus isolates, SEO virus is the most genetically
homogeneous. Isolates of SEO virus, regardless of their geographic origin,
display M segment nucleotide and deduced amino acid sequence homologies of
approximately 95%, and 99%, respectively (41,47). A reported exception, the
R22 isolate from China, had a slightly lower homology; however, the
original data suggest that an error in the nucleotide sequence, resulting
in a frame shift reading error, may account for almost all of the
additional changes. PUU virus isolates vary the most, with M segment
nucleotide and amino acid sequence homologies of 83% and 94% observed
between a Finnish and Russian isolate. HTN virus also appears to be quite
stable in nature. Comparing the M segment sequences of prototype HTN virus
(from Apodemus) and those of two human isolates obtained at a 6-year
interval from HFRS patients in Korea produced nucleotide and deduced amino
acid sequence homologies of 94% and 97%, respectively (48). For SN virus,
comparing the complete M or S segment sequences of three strains from
California or New Mexico produced homologies of 87% to 99%. Partial
nucleotide sequence comparisons of the M or S segments of SN viruses from
adjacent counties in California, detected in deer mice captured 19 years
apart, were 97.5% homologous (49). Similarly, a retrospective analysis of
archived tissue samples collected in Mono County, California, in 1983
showed viruses with partial M and S segment nucleotide sequence homologies
of about 87% with SN from an 1993 HPS patient from New Mexico (50). In all
cases, the amino acid sequences encoded by these genes differed between
cognate proteins by much less than 5%. These values are similar to those
observed among strains of HTN virus. Studies have just begun to appear in
which the nature of quasispecies in natural rodent hosts is defined
(43,51). Such investigations should provide more definitive data concerning
the genetic diversity among hantaviruses in nature.
Evolution of Hantaviruses
Phylogenetic trees derived by comparing complete or partial S (Figure), M,
or L segment nucleotide sequences (41,52,53) show two major lineages of
hantaviruses, one leading to HTN, SEO, Thailand, and DOB viruses, and one
leading to PUU, Prospect Hill, SN, and other New World hantaviruses. TPM
virus, the first hantavirus isolated in cell culture (54), may be the most
antigenically and genetically disparate member of the genus; however,
comparison of the complete nucleotide sequence of the TPM S segment (A.
Toney, B. Meyer, C. Schmaljohn, unpub. data) suggests that TPM virus is
more closely related to HTN, SEO, and DOB viruses than to any of the other
viruses in the genus (Figure). Nucleotide sequence homologies of the M and
S segments of any two hantaviruses have approximately the same degree of
divergence between each of the three segments, which suggests similar
evolutionary rates for these two gene segments. A slightly higher homology
among L segments sequenced to date perhaps indicates a greater need for
conservation of either RNA or protein functions (47). Point mutations
appear to account for most of the genetic drift among hantaviruses.
Recombination has not been reported for hantaviruses, although segment
reassortment within a particular species appears common (52,55). The
exchange of gene segments is suggested to be nonrandom, with a higher
propensity for M segment swapping, than for S or L (55). Whether it
contributes to the pathogenesis of hantaviruses is not known, but
reassortment certainly provides an avenue for more rapid accumulation of
changes than could occur by point mutation. There is no evidence that
reassortment can occur between different species of hantaviruses; however,
this has not been studied systematically.
Murid rodents have probably harbored inapparent hantavirus infections for
thousands, perhaps millions of years. It is likely that the genus
Hantavirus evolved in the Old World and that viruses were carried by
rodents across the Bering land bridge when they migrated during the
Oligocene, and into South America in the Pliocene (71). Humans are
incidental hosts, the victims of spillover infections from the natural host
rodents. One of the two major forms of hantaviral diseases is endemic in
each hemisphere. Both HFRS and HPS can be divided into distinct clinical
subtypes, and the viral strain is a key determinant of the severity and
nature of the clinical abnormalities. Not covered in this review are
clinical studies of HFRS and HPS patients, which suggest that pathogenesis
may be immunologic and may be mediated by cytokine responses (72). New
outbreaks with novel hantavirus strains are still being uncovered,
especially in South America. However, the largest clinical caseload and
largest number of deaths occur in Asia and Europe.
Dr. Schmaljohn is chief, Department of Molecular Virology, USAMRID. Current
research interests include the development of molecular vaccines for
hantaviruses, filoviruses, and flaviviruses.
Dr. Hjelle has been active in studies of the molecular biology, evolution,
epidemiology, and clinical aspects of hantavirus disease. His laboratory is
a reference diagnostic center for hantavirus infections of humans and
animals and has recently received funding to develop innovative vaccine
strategies against HPS and other emerging viral diseases.
Address for correspondence: Connie Schmaljohn, Virology Division, USAMRID,
Fort Detrick, Frederick, MD 21702-5011; fax: 301-619-2439; e-mail:
cschmaljohn@detrick.army.mil
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