Family Arenaviridae - Viruses And Human Disease

RNAs are ambisense in character. The S segment corre-

the lungs, which can result in respiratory death. This loss of

sponds to the bunyavirus S and M segments linked tail to

fluids from the intravascular compartment also leads to an

tail in an ambisense arrangement (Fig. 4.1). The L segment

increase in the hematocrit (the percentage of blood volume

corresponds to the L segments of bunyaviruses but with the

occupied by red blood cells). Early attempts to decrease the

addition of a second gene, encoding a protein called Z, in an

hematocrit by supplying fluid intraveneously simply exac-

ambisense orientation. Expression of the encoded genes fol-

erbated the pulmonary edema. Even with the best treatment

lows an ambisense strategy as described for some of the bun-

today, however, the mortality rate is still very high.

yaviruses. The mRNA for one gene is synthesized from the

It is clear that hantaviruses are widely distributed around

genomic RNA and is expressed early, whereas the mRNA

the world and have been present in their rodent hosts for a very

for the second gene is synthesized from the antigenomic or

long time. Although many are capable of causing serious ill-

vcRNA and is expressed late (Fig. 4.27). As in the bunya-

ness in man, the number of human cases is fortunately small.

viruses, synthesis of arenavirus mRNA occurs in the cyto-

However, there is always the fear that one of these viruses

plasm using a primer that is snatched from cellular mRNAs,

might acquire the ability to spread more readily from human

there is a secondary structure in the RNA between the two

to human and thereby become a more serious problem.

ambisense genes that causes termination of transcription,

and the mRNAs are not polyadenylated.

FAMILY ARENAVIRIDAE

The genomic S RNA is the template for synthesis of the

mRNA for N, and N is therefore expressed early after for the

A listing of the 22 currently recognized arenaviruses is

synthesis of infection. Because N is required for the replica-

found in Table 4.12. They can be grouped on the basis of

tion of the viral RNA, as is the case for all (-)RNA viruses,

sequence alignments and serological cross-reactions into

this arrangement is necessary if the virus is to replicate.

four clades. The Old World viruses form a single clade,

The mRNA for the glycoproteins G1 and G2 is transcribed

whereas the New World viruses group into three different

from the antigenomic copy of S and is therefore expressed

clades, called A, B, C. The genomes consist of two segments

late. The glycoproteins are produced as a polyprotein that is

of (-)RNA which together total about 11 kb. As for other

cleaved in a process that is similar to what happens in the

(-)RNA viruses, the genomic RNA is present in helical

bunyaviruses. There is an N-terminal signal sequence that

nucleocapsids. Budding to acquire the viral envelope is from

leads to the insertion of the precursor called GPC into the

the plasma membrane (Fig. 2.25B). Virions are spherical but

endoplasmic reticulum. The signal sequence is removed by

variable in size, with diameters ranging from 50 to 300 nm.

cellular signalase. The resulting precursor is cleaved by the

It is believed that the number of RNA segments incorpo-

cellular subtilase SKI-1/S1P, the same enzyme that processes

rated into a virus particle is not fixed. Multiple copies of the

the hantavirus glycoprotein precursor, into the N-terminal

genome segments may be present in virions and this may

GN (sometimes called G1 or GP-1) and the C-terminal GC

account, in part if not entirely, for the variation in the size of

(sometimes called G2 or GP-2). GN and GC remain associ-

virions. Also incorporated into the budding virions are vari-

ated as a heterodimer. Only GC has a transmembrane anchor,

able numbers of ribosomes. The name for the family comes

and the process thus resembles what happens in HA of influ-

from the Latin word for sand (arena) because the ribosomes

enza or F of paramyxoviruses where a type I glycoprotein is

in the virions give them a grainy appearance. Why ribo-

cleaved into N-terminal and C-terminal subunits that remain

somes are incorporated into virions is not known, as they

associated by noncovalent bonds.

do not appear to serve a useful function for viral assembly

Producing the glycoproteins late has the effect of delay-

or replication.

ing virus assembly. This allows RNA amplification to pro-

The arenaviruses share many features with the hantavi-

ceed for an extended period of time before it is attenuated by

ruses. They are associated with rodents and have coevolved

the incorporation of nucleocapsids into virions. Attenuation

with them, as have the hantaviruses. They are transmitted to

of RNA synthesis is also effected by the Z protein.

humans by contact with aerosolized rodent urine or feces;

In the case of the L segment, the mRNA for protein L

many cause very serious illness, often hemorrhagic fever,

is produced early by synthesis from the genomic RNA.

with a high mortality rate. Their genome organization and

Proteins L and N are necessary and sufficient for RNA repli-

mode of replication has much in common with the hantavi-

cation, and this orientation of the genes is necessary for virus

ruses, as described later.

replication. The mRNA for protein Z mRNA is transcribed

from the antigenomic and thus Z is expressed late, after rep-

lication of the RNA begins. Z is a small protein of about

Genome Organization and Expression

11 kDa that has multiple functions in viral replication. It has

The genome organization of an arenavirus is illustrated

a RING finger motif and binds zinc. It downregulates RNA

in Fig. 4.27. Arenavirus genomes consist of two segments

replication and the synthesis of mRNAs. It is also required

of RNA, naturally called L(arge) and S(mall). Both genomic

for budding of virions. In fact, expression of Z in the absence

TABLE 4.12 Arenaviridae

Virus name

Natural rodent

Disease in

World

host(s)b

Genus/

members

abbreviation

Transmission

humans

distribution

Old World Arenaviruses

Urine, salivac

Aseptic meningitis

Worldwide

Lymphocytic

LCMV

Mus musculus

choriomeningitis

Lassa

LASV

Mastomys sp.

Urine, saliva

Hemorrhagic fever (HF)

West Africa

Mopeia

MOPV

Mastomys natalensis

Urine, saliva

Nonpathogenic?

Mozambique,

Zimbabwe

Mobala

MOBV

Praomys sp.

Central African

Republic

Ippy

IPPYV

Arvicanthis sp.

Nonpathogenic?

Central African

Republic

New World Arenaviruses

Group Ad

Tamiami

TAMV

Sigmodon hispidus

Urine, saliva

Nonpathogenic?

Florida (U.S.)

Whitewater Arroyo

WWAV

Neotoma albigula

Urine, saliva

Three fatal cases of

Western United States

ARDS in Californiae

Bear Canyon

BCNV

Peromyscus californicus

Urine, saliva

Western United States

Paraná

PARV

Oryzomys buccinatus

Urine, saliva

Nonpathogenic?

Paraguay

Flexal

FLEV

Oryzomys ssp.

Urine, saliva

Nonpathogenic?

Brazil

Pichinde

PICV

Oryzomys albigularis

Urine, saliva

Nonpathogenic?

Colombia

Pirital

PIRV

Sigmodon alstoni

Urine, saliva

Nonpathogenic?

Venezuela

Allpahuayo

ALLV

Oecomys bicolor and

Urine, saliva

Nonpathogenic?

Northeastern Peru

O. paricola

Group B

Guanarito

GTOV

Zygodontomys brevicauda

Urine, saliva

Venezuelan HF

Venezuela

Junin

JUNV

Calomys musculinus

Urine, saliva

Argentine HF

Argentina

Machupo

MACV

Calomys callosus

Urine, saliva

Bolivian HF

Bolivia

Sabiá

SABV

Unknown

???

Isolated from a fatal case, Brazil

and has caused two severe

laboratory infections

Amapari

AMAV

Oryzomys capito,

Urine, saliva

Nonpathogenic

Brazil

Neacomys guianae

Artibeus spp. bats f

Tacaribe

TCRV

Has been isolated

Nonpathogenic

Trinidad

from mosquito

Cupixi

TCRV

Oryzomys capito

Nonpathogenic

Brazil

Group C

Latino

LATV

Calomys callosus

Bolivia

Oliveros

OLVV

Bolomys obscurus

Argentina

LCMV is the type virus of the family.

Most of these viruses cause chronic infections in their natural rodent hosts.

At least one case is known where several recipients contracted LCMV after organ transplants from an asymptomatic donor.

White Water Arroyo, Tamiami, and Bear Canyon viruses have nucleoprotein genes related to those of Pichinde and Pirital in Group A, but glycoprotein

genes related to Tacaribe, Junin, and Sabiá in Group B.

ARDS, acute respiratory distress syndrome. Until these cases in 19992000, WWAV was not known to cause human illness.

Originally isolated from fruit-eating bats, but subsequent isolation attempts from bats have failed.

Source: Fields et al. (1996), Table 1 on p. 1522; Porterfield (1995), Table 11.1 on p. 228; and recent information from Fauquet et al. (2005).

Lassa fever virus S RNA (3417 nt)

Gc (234aa) Gn (256aa)

Translation

Cleavage

GPC mRNA

mRNA synthesis

vcRNA

Replication

Genome RNA

mRNA synthesis

NmRNA

Translation

N protein (570 aa)

Z (99aa)

Translation

Lassa fever virus L RNA (7279 nt)

Z mRNA

mRNA synthesis

vcRNA

Replication

59 Genome RNA

mRNA synthesis

LmRNA

Translation

L protein (2218 aa)

FIGURE 4.27 Genome organization and replication strategy of an arenavirus, Lassa fever virus. The genome consists

of two segments of RNA, L and S. Both segments are expressed using an ambisense strategy. The nucleocapsid protein

mRNA is synthesized from the 3¢ end of the genomic S RNA, while the GPC mRNA is synthesized from the vc S RNA.

A similar strategy occurs with the L segment. In this case, however, more than 95% of the coding capacity is used for the

L protein, the RNA dependent RNA polymerase. Also note that the 5¢ nontranslated region of L mRNA is 157 nt, which

is unusually long for an arenavirus. The Z protein is a so-called "ring finger protein" that is involved in regulation of

transcription and replication. Drawn from data in Lukashevich et al. (1997) and Clegg et al. (1990).

of other viral proteins results in the formation of virus-like

organization and expression, the association with a sin-

particles, and Z has a role in budding analogous to the role

gle rodent species, and the nature of the disease caused in

played by the M proteins of other (-)RNA viruses or the Gag

humans all suggest that the arenaviruses are closely related

protein of retroviruses. It has been found that Z recruits a

to the hantaviruses. A reasonable hypothesis is that the are-

cellular protein called Tsg101 to the site of budding. Tsg101

naviruses arose from the hantaviruses by fusion of the S

has been shown to be required for budding of (at least) two

and M segments to form one segment, which allowed finer

arenaviruses, of HIV, and of Ebola virus. Tsg is a compo-

control of the virus life cycle.

nent of the vacuolar protein sorting machinery of the cell and

The cellular receptor for entry of many arenaviruses is

α-dystroglycan, which plays a critical role in cell-mediated

is therefore active in promoting cellular budding pathways.

Z was originally thought to be a nonstructural protein and

assembly of basement membranes. This protein is widely

was called NS. It is now known to be present in the virion.

distributed in animals and many arenaviruses have a broad

The stoichiometry of proteins in virions of Lassa virus was

tissue tropism. For example, Lassa infection of humans

found to be 1:160:60:60:20 for L:N:GN:GC:Z.

results in high virus titers in spleen, lung, liver, kidney,

heart, placenta, and mammary gland. Viruses that have

a high binding affinity for α-dystroglycan replicate pref-

Natural History and Diseases

erentially in the white pulp of the spleen and infect large

The natural history of the arenaviruses is very similar to

numbers of lymphocytes that are important in the immune

that of the hantaviruses (Table 4.12). They establish a per-

response to viral infection. The ability of these lymphocytes

sistent infection in a single rodent host. Many cause hemor-

to act as antigen-presenting cells results in impairment of

rhagic fever in humans following infection by aerosolized

immune responses resulting in a generalized immunosup-

virus excreted in urine or feces. They appear to have co-

pression. Such viruses are more virulent than those that bind

less avidly to α-dystroglycan. Immunosuppression may be

evolved with their hosts: An evolutionary tree of arenavi-

ruses resembles the tree that describes their rodent hosts, as

important for the establishment of persistent infections in

was true of the hantaviruses. The many similarities in genome

the rodent host, in which the virus does not cause disease.

In humans, however, immunosuppression may lead to much

damage and may be deaf because of such damage. The full

more serious illness.

extent of Lassa disease is not known because most Africans

The arenaviruses can be divided into Old World viruses

infected by the virus do not seek help and there is little

and New World viruses (Table 4.12). Because of their asso-

monitoring of the disease. However, estimates range from

ciation with a single rodent species, their geographic range

100,000 to 300,000 cases per year.

is restricted to that of their host, and rodents have a restricted

Lassa virus was first isolated in 1969 when a nurse in a

range. The exceptions are rodents that have been distributed

rural mission hospital in Nigeria became infected. She was

widely by humans such as the house mouse and the urban

transported to Jos, Nigeria where several health care workers

rat. Many arenaviruses cause hemorrhagic fever in man with

became infected. Serum samples were sent to the United States

significant mortality rates (Table 4.12).

and a well-known virologist at the Yale Arbovirus Research

Unit, Dr. Jordi Casals, became infected with the virus while

working with it and became very seriously ill. He eventu-

Lymphocytic Choriomeningitis Virus

ally recovered but later that same year a technician in another

Lymphocytic choriomeningitis virus (LCMV), the proto-

laboratory at Yale became infected with Lassa fever virus

type virus of the family, is associated with the house mouse

and died, whereupon Yale ceased to work with the virus.

Mus domesticus and Mus musculus. This virus is widespread

The containment facilities in 1969 were not of the quality

in Europe, along with its host, and spread to the Americas

of those in current use and virologists in those days literally

with the (inadvertent) introduction of the house mouse by

took their lives in their hands when working with dangerous

European travelers. LCMV has been intensively studied in

agents. The study of virology owes a great deal to the courage

the laboratory as a model for the arenaviruses, in part because

exhibited by these earlier workers.

it is less virulent for humans than many arenaviruses, and

Lassa has been imported to the United States on at least

in part because its natural host is widely used as a labora-

one occasion in the form of a viremic individual. A resident

tory model for animal work. Mice are small, reproduce rap-

of Chicago attended the funerals of relatives in Nigeria who

idly, and there is a great deal of experience in maintaining

had died of Lassa fever and became infected there. On return

this animal in the laboratory. LCMV is widespread, often

to Chicago he began suffering symptoms of Lassa fever but

being present in colonies of laboratory mice even without

the local hospitals were unable to diagnose the cause of his

overt introduction. It is also present in wild mice and may be

disease, being unfamiliar with it. He eventually died of Lassa

present in pets such as hamsters.

fever, but fortunately there were no secondary cases.

LCMV infection of humans usually results in mild or even

inapparent illness, although serious illness can result with

New World Group B Viruses

occasional mortality. In a recent incident, a woman had been

infected with LCMV from a pet hamster. She suffered no

Several South American arenaviruses belonging to

apparent illness from the viral infection but died of an unre-

Group B are very important disease agents because they

lated cause, a stroke. Her liver, lungs, and kidneys were har-

cause large outbreaks of hemorrhagic fever with high mor-

vested for transplantation. Transplantation of liver, lungs, and

tality rates. The names of a number of these viruses and the

kidney requires immunosuppression so that the transplanted

places where they are found are shown in Fig. 4.28. They

organs are not rejected. Three patients receiving the liver,

include Junín virus (causative agent of Argentine hemor-

lungs, and a kidney developed overwhelming infection by

rhagic fever), Machupo virus (Bolivian hemorrhagic fever),

LCMV and died. A fourth patient who received a kidney also

Guanarito virus (Venezuelan hemorrhagic fever), and Sabiá

became quite ill from LCMV infection but survived, aided by

virus (cause of an unnamed disease in Brazil). The diseases

reduction in the immunosuppressive drugs being given.

caused by these viruses are often referred to as emerging

diseases because the number of human cases has increased

with development and expanding populations. The increas-

Lassa Virus

ing number of cases results from development of the pam-

The rodent reservoir of Lassa virus is Mastomys natalensis.

pas or other areas for farming, bringing humans in closer

Lassa virus causes outbreaks in West Africa of an often fatal

association with the rodent reservoirs. Furthermore, the stor-

illness in humans called Lassa fever. The mortality rate aver-

age of grain near human habitation results in an increase in

ages 1015% but may be as high as 60% in some outbreaks.

the local rodent population, and plowing of the fields leads

The virus has a broad tissue tropism and symptoms include

to the production of aerosols which may transmit the dis-

fever, myalgia, and severe prostration, often accompanied

ease to humans. An attenuated virus vaccine against Junín

by hemorrhagic or neurological symptoms. Development of

virus has been developed and is widely used in populations

hemorrhagic symptoms indicates a poor prognosis and death

at risk. The vaccine is effective and has reduced dramati-

often follows. Fatal infection is also characterized by higher

cally the number of cases of Argentine hemorrhagic fever.

viral loads. Survivors of severe infection often suffer nerve

No vaccines are in use for the other viruses, however.

Bear Canyon (2002)

(Peromyscus californicus)

Tamiami (1964)

(Sigmodon hispidus)

Guanarito (1990)

(Zygodontomys brevicauda)

Whitewater Arroyo (1995)

(Neotoma albigula)

Tacaribe (1956)

(Artibeus Bats)

Pichindé (1965)

Pirital (1995)

(Oryzomys albigularis)

(Sigmodon alstoni)

Allpahuayo (1997)

Amaparí (1964)

(Oecomys bicolor)

(Necomys guianae)

Flexal (1975)

(Oryzomys spp.)

Cupixi (1970)

(Oryzomys capito)

Machupo (1963)

(Calomys callosus)

Sabiá (1990)

Latino (1965)

host unknown

(Calomys callosus)

Paraná (1965)

Oliveros (1990)

(Oryzomys buccinatus)

(Bolomys obscurus)

Virus Isolates

Junín (1958)

Before 1960

(Calomys musculinus)

1960 to 1970

1975

1990 on

FIGURE 4.28 Arenavirus isolates in the New World. Also shown are the year of first isolation, and the rodent host of

each virus where known. Adapted from Peters (1998b), Figure 1.

Agents Causing Hemorrhagic Fevers

New World Group A Viruses

in Humans

Three arenaviruses have been isolated in the United

States, Whitewater Arroyo virus, present in the Southwest,

Many viruses, belonging to several different families,

Bear Canyon virus in California, and Tamiami virus,

have been described that cause hemorrhagic fever in humans.

present in Florida (Fig. 4.28). None of these viruses, all

Table 4.13 contains a listing of many of these viruses. These

of which belong to Group A, had been known to cause ill-

viruses include members of the Arenaviridae, Bunyaviridae,

ness in humans until very recently. In 19992000, three

Filoviridae, and Flaviviridae. Many cause severe disease

Californians died following infection by Whitewater

with high mortality, but although the disease is severe, with

Arroyo virus. The disease these three suffered was ARDS

the exception of some arenaviruses, survivors have few

(acute respiratory disease syndrome), although two also

sequelae. The dramatic symptom of profuse bleeding has

had hemorrhagic manifestations. Thus, like the hantavi-

excited the purple prose of many lay authors, best illustrated

ruses, the U.S. arenaviruses may cause isolated cases of

by recent discussions of Ebola virus, and struck terror in

serious illness. There are also a number of Group B viruses

native populations. With the exceptions of yellow fever virus

in South America (Table 4.12), but these are not known to

and Junín virus, there are no vaccines, and treatments are

cause disease in humans.

primarily supportive, although ribavirin therapy holds some

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