Family: Arenaviridae

Genus: Mammarenavirus


Distinguishing features

Mammarenaviruses typically infect muroid rodents (members of the superfamily Muroidea). One mammarenavirus, Tacaribe virus (TCRV), was found in phyllostomid bats and lone star ticks (Downs et al., 1963, Sayler et al., 2014). In contrast to antennaviruses and reptarenaviruses, but similar to hartmaniviruses, mammarenaviruses encode a stable signal peptide (SSP) that remains associated with the glycoprotein (GP) complex (Buchmeier et al., 1987, Kunz et al., 2003, Lenz et al., 2001, Bederka et al., 2014, Eichler et al., 2003, York et al., 2004). 



Virions are spherical or pleomorphic, 50–200 nm in diameter, with dense lipid envelopes (Figure 1. Mammarenavirus). The virion surface layer is covered with club-shaped projections, 8–10 nm in length and 10 nm apart, with distinctive stalk and head regions. These projections are made of trimeric spike structures of two virus-encoded membrane glycoprotein (GP) subunits. Isolated ribonucleoprotein (RNP) complexes are organized in “beads-on-a-string”-like structures. Internal granules within virions are morphologically similar to host ribosomes (Li et al., 2016, Neuman et al., 2005, Buchmeier 2002, Charrel and de Lamballerie 2003, Jay et al., 2005, Meyer et al., 2002, Dalton et al., 1968, Gonzalez et al., 2007). Tomographic 3D reconstructions of Lassa virus (LASV) particles and cryo-electron micrographic images of lymphocytic choriomeningitis virus (LCMV), Pichindé virus (PICHV), and TCRV particles identified two interior layers beneath the inner leaflet of the virion lipid bilayer (Li et al., 2016, Neuman et al., 2005)

Figure 1. Mammarenavirus. (A) Electron microscopic images of lymphocytic choriomeningitis virus (LCMV). The thin section shows several virions with internal inclusion bodies budding from the surface of an infected baby hamster kidney (BHK-21) cell. (B) Cryo-electron microscopic images of purified unstained LCMV particles frozen in vitreous ice. The bar indicates 100 nm. (C) Cryo-electron microscopy of frozen-hydrated Tacaribe virus (TCRV). The heterogeneous size and shape of these virions is typical of all of the viruses examined. (D) LCMV (strain WE) budding into intracellular spaces in the adrenal cortex of a guinea pig infected 8 days earlier. (Courtesy R. Milligan, J. Burns, and M. Buchmeier). 

Physicochemical and physical properties

Virion molecular mass, Mr, has not been determined, but its sedimentation coefficient, S20,w, is 325–500 S and its buoyant density in sucrose, CsCl, and amidotrizoate compounds is about 1.17–1.18 g cm−3, 1.19–1.20 g cm−3, and 1.14 g cm−3, respectively. Virions are relatively unstable in vitro and are rapidly inactivated below pH 5.5 and above pH 8.5. Virus infectivity is inactivated at 56 °C, by treatment with organic solvents or detergents, or by exposure to UV- and gamma-irradiation (Rawls and Buchmeier 1975, Elliott et al., 1982, Mitchell and McCormick 1984, Pfau 1965)

Nucleic acid

Virions contain 2 ambisense single-stranded RNA segments that are encapsidated independently. The termini of the RNAs contain inverted complementary sequences encoding transcription and replication initiation signals. The 3′-end untranslated region (UTR) of the genome and antigenome segments contain the genomic and antigenomic promoters, respectively, that direct RNA replication and gene transcription (Perez et al., 2003, Hass et al., 2006). No poly(A) tracts are present at the 3′-termini. The 5′- and 3′-ends of the large (L) and small (S) RNA segments contain conserved reverse-complementary sequences of 19 to 30 nucleotides at each extremity (Auperin et al., 1982a, Auperin et al., 1982b). These termini are predicted to form panhandle structures through base pairing (Salvato et al., 1989, Harnish et al., 1993, Young and Howard 1983). Although the genomic RNAs are thought to be present in virions in the form of circular nucleocapsids, the genomic RNA is not covalently closed. The virus RNAs are not present in equimolar amounts in the virions, apparently due to the packaging of multiple RNA molecules per virion. For example, more than one S RNA molecule might be packaged per virion  (Romanowski and Bishop 1983). 


Mammarenaviruses express 4 structural proteins (Table 1. Mammarenavirus). The most abundant structural protein in an arenavirion is nucleoprotein (NP), which encapsidates the virus genomic segments. The least abundant protein is the RNA-directed RNA polymerase (L), which mediates virus genome replication and transcription. The zinc-binding protein (Z) functions as a matrix protein. Unlike reptarenavirus Z, mammarenavirus Z (with the exception of TCRV Z) possesses late budding motifs and an N-terminal glycine residue typically associated with myristoylation for membrane anchoring. The preproprotein GPC (about 75–76 kDa) is cleaved by the signal peptidase to generate a stable signal peptide (SSP) and a precursor protein that is processed by the cellular protease subtilisin kexin isozyme-1(SKI-1)/site 1 protease (S1P) to generate the mature virion surface glycoproteins (GP1 or G1, GP2 or G2).

Table 1. Mammarenavirus Location and functions of arenavirus structural proteins. 


Location, mass, and function

Nucleoprotein (NP)

Structural virion protein (about 60–68 kD). Component of the RNP inside virions. Oligomerizes and encapsidates virus genomic and antigenomic segments. Functions as an exoribonuclease and serves as an interferon antagonist. Interacts with Z (Buchmeier 2002, Martínez-Sobrido et al., 2006, Brunotte et al., 2011, Hastie et al., 2011a, Hastie et al., 2011b, West et al., 2014). 

Glycoprotein (GP)

Structural virion glycoprotein (about 50–60 kD). Produced via proteolytic cleavage from the precursor GPC (about 70–80 kD). Cleavage produces heterotrimers consisting of GP1, GP2, and stable signal peptide (SSP). Inserts into virion membranes as a tripartite heterotrimeric GP complex. As a class I fusion machine, GP mediates cell-surface and internal receptor binding (via GP1), virion-cell membrane fusion and, thereby, virion cell entry (via GP2) (Buchmeier et al., 1987, Kunz et al., 2003, Lenz et al., 2001, Bederka et al., 2014, Eichler et al., 2003, York et al., 2004, Hastie et al., 2017). 

RNA-directed RNA polymerase (L)

Structural virion protein (about 250–450 kD). Component of the RNP inside virions. Oligomerizes and mediates transcription and replication of arenavirus RNA segments. Mediates cap-snatching for virus mRNA capping (Kranzusch et al., 2010, Reguera et al., 2016, Peng et al., 2020). 

Zinc-binding protein (Z)

Structural virion protein (about 10–14 kD). As a zinc-binding virion matrix protein, Z self-associates and polymerizes at membranes, mediates virion assembly and budding, interacts with NP and GPC, and negatively regulates transcription. Z also serves as an interferon antagonist (Perez et al., 2003, Fehling et al., 2012, Hastie et al., 2016, Capul et al., 2007, Perez et al., 2004, Strecker et al., 2006, Shao et al., 2018, Urata et al., 2009, Salvato and Shimomaye 1989). 


Lipids represent about 20% of virion dry weight and are similar in composition to those of the host plasma membrane. Z and SSP of mammarenaviruses are myristoylated at glycine residue 2. Myristoylation is critical for Z to bind to lipid membranes and thus, for virion budding, whereas myristoylation of SSP is critical for membrane fusion (York et al., 2004, Perez et al., 2004). 


Carbohydrates in the form of complex glycans are present on GP1 and GP2 and represent up to 8% of virion dry weight (Grutadauria et al., 1999, Bonhomme et al., 2011). These carbohydrates serve as a shield for virions from host antibodies (Sommerstein et al., 2015, Watanabe et al., 2018)

Genome organization and replication 

The S and L RNAs of mammarenaviruses each encode two proteins in non-overlapping open reading frames (ORF) of opposite polarities (ambisense coding arrangement) that are separated by non-coding intergenic regions (IGRs) (Figure 2. Mammarenavirus).  The S RNA encodes NP in the virus genome-complementary sequence, and GPC in the virus genome-sense sequence. The L RNA encodes L in the virus genome-complementary sequence, and Z in the virus genome-sense end sequence (Salvato and Shimomaye 1989). The IGRs form one or more energetically stable stem-loop (hairpin) structures (Auperin et al., 1984a, Wilson and Clegg 1991, Auperin et al., 1984b) and function in structure-dependent transcription termination (Meyer and Southern 1993, Tortorici et al., 2001, Meyer and Southern 1994) and in virion assembly and budding (Pinschewer et al., 2005) (Figure 2. Mammarenavirus). 

Figure 2. MammarenavirusSchematic representation of the bisegmented genome organization of lymphocytic choriomeningitis virus. The 5′- and 3′-ends of both segments (S and L) are complementary at their termini, likely promoting the formation of circular ribonucleoprotein complexes within the virion. GPC, glycoprotein precursor; L, RNA-directed RNA polymerase; NP, nucleoprotein; Z, zinc-binding matrix protein. Intergenic regions (IGRs), which form hairpin structures (not shown), separate open reading frames. 

Mammarenavirus infection begins with virion attachment to cell-surface receptors (e.g., dystroglycan 1 [DAG1] or transferrin receptor [TFRC]) and entry via the endosomal route (Martinez et al., 2007, Vela et al., 2007, Borrow and Oldstone 1994, Radoshitzky et al., 2007, Cao et al., 1998, Raaben et al., 2017, Glushakova and Lukashevich 1989) (Figure 3. Arenaviridae). pH-dependent fusion with late endosomes releases the virion RNP complex into the cytoplasm. In the case of Lassa virus (LASV), entry involves a pH-dependent switch from DAG1 to an intracellular receptor, LAMP1 (Jae et al., 2014).  

The virus RNP directs both RNA genome replication and gene transcription (Meyer et al., 2002). During replication, L reads through the IGR transcription-termination signal and generates uncapped antigenomic and genomic RNAs (Leung et al., 1977). Because these RNAs contain a single non-templated G at the 5′-ends  (Garcin and Kolakofsky 1990, Raju et al., 1990), replication initiation might involve a slippage mechanism of L on the nascent RNA (Garcin and Kolakofsky 1992). Because of the ambisense coding arrangement, only mRNAs encoding NP or L can be synthesized from genomic RNAs. Transcription of mRNAs encoding GPC or Z occurs only after the first round of virus replication, during which S and L antigenomes are produced. 

Mammarenavirus proteins are synthesized from subgenomic capped mRNAs. Arenavirus mRNAs are not polyadenylated (Meyer and Southern 1993, Singh et al., 1987, Southern et al., 1987). The 5′-ends  of virus mRNAs contain several non-templated bases downstream of the 5′-cap structure, suggesting that mammarenaviruses use either polymerase slippage or a cap-snatching mechanism similar to that used by other members of the subphylum Polyploviricotina (Garcin and Kolakofsky 1990, Raju et al., 1990, Meyer and Southern 1993). Cap-snatching would require an endonuclease presumed to be present in the N-terminal part of L that cleaves cellular mRNAs to generate a cap leader that is subsequently used to prime arenavirus transcription (Kranzusch et al., 2010, Peng et al., 2020) The 3′-termini of the mRNAs have been mapped to locations in the IGRs. 

The mammarenavirus GPC polyprotein matures in the lumen of the endoplasmic reticulum, where its SSP is co-translationally cleaved and GPC is extensively N-glycosylated. GPC is thought to oligomerize prior to proteolytic processing by the subtilisin kexin-isozyme-1/site-1 protease. Proteolytic maturation of GPC into GP1 and GP2 and trafficking of GP1/GP2 from the endoplasmic reticulum to the cell surface is dependent on the SSP. Virion budding occurs from the cellular plasma membrane, thereby providing the virion′s envelope. Ribosome-like structures are observed within virions, but the origin and composition of these structures have not been elucidated (Dalton et al., 1968, Eichler et al., 2004, Perez et al., 2003, Strecker et al., 2003). Incorporation of these structures does not seem to be required for mammarenavirus replication and infectivity (Leung and Rawls 1977)

During mammarenavirus infection, intratypic reassortant progeny can be formed, including diploid (or multiploid) types with respect to the genomic RNA segments. Evidence for reassortment between viruses of different species (e.g., LASV and Mopeia virus [MOPV]) has also been obtained (Lukashevich 1992)


The reservoir hosts of almost all mammarenaviruses are rodents of the superfamily Muroidea (Bowen et al., 1997, Hugot et al., 2001). LCMV is found in the house mouse and has a worldwide distribution, whereas the African mammarenaviruses are found mainly in rodents belonging to the Mastomys and Praomys genera (all family Muridae, subfamily Murinae). New World mammarenaviruses are mostly found in rodents belonging to the murid subfamily Cricetidae. An exception is TCRV, which was isolated from Jamaican fruit-eating bats (Chiroptera: Phyllostomidae: Artibeus jamaicensis Leach, 1821) and great fruit-eating bats (Artibeus lituratus Olfers, 1818) in the Caribbean (Downs et al., 1963) and from lone star ticks (Ixodida: Ixodidae: Amblyomma americanum (Linnaeus, 1758)) in Florida (Sayler et al., 2014). The geographic range of mammarenaviruses is generally much more restricted than that of their cognate rodent host-reservoirs (Gonzalez et al., 2007, Salazar-Bravo et al., 2002a, Salazar-Bravo et al., 2002b)

Typically, mammarenaviruses induce persistent, frequently asymptomatic infections in their reservoir hosts, which are characterized by chronic viremia and viruria (Bowen et al., 1997, Hugot et al., 2001). Chronic infections are suspected to be caused by suppressed host immunity. The chronic carrier state in rodents usually results from vertical transmission (exposure to infectious virus early in ontogeny) or horizontal transmission (exposure to virus later in life through aggressive, venereal behavior or via oral contamination and/or aerosol routes) (Mills et al., 1992, Webb et al., 1975)

Most mammarenaviruses do not normally infect mammals other than their preferential reservoir hosts. However, some mammarenaviruses may cross species barriers and eventually be pathogenic and often highly virulent for humans. Humans become infected via direct contact with infected muroid rodents or their products (droppings, urine, ingestion of contaminated food, or exposure to broken skin or mucous membranes) or via indirect contact by inhalation of infected droplets from contaminated rodent excreta, secreta, or body parts caught in mechanical harvesters (Charrel and de Lamballerie 2003). Peridomestic rodents are also part of the diet in certain populations. Consequently, handling of infected rodents and consumption of contaminated food could be another route of virus transmission (Keenlyside et al., 1983). Person-to-person transmission of mammarenaviruses is rare but possible by direct contact with body fluids or excreta of infected patients, but regularly occurs by nosocomial routes (Johnson 1965, Paweska et al., 2009, Fisher-Hoch et al., 1995).

Human disease caused by mammarenaviruses include Lassa fever (LF) in Western Africa (caused by LASV). Lujo virus (LUJV) has caused a small but severe disease outbreak in Southern Africa. Junín virus (JUNV) causes Argentinian hemorrhagic fever (AHF) in an increasingly large area of Argentina; MACV has caused isolated outbreaks of Bolivian hemorrhagic fever (BHF) in Bolivia; and Guanarito virus (GTOV) is the etiologic agent of Venezuelan hemorrhagic fever (VeHF) in Venezuela. Sabiá virus (SBAV) and Chapare virus (CHAPV) have been isolated from fatal human infections in Brazil and Bolivia, respectively (Radoshitzky et al., 2018). Cases of New World mammarenavirus infection have predominantly occurred among male agricultural workers who have come into contact with infected rodents during harvest season when rodent populations are active (Radoshitzky et al., 2018). Human infection with LCMV may occur in some rural and urban areas with high rodent populations and has been acquired from pet hamsters (Hirsch et al., 1974). Organ transplants from LCMV-infected individuals have resulted in at least 10 human deaths in the USA since 1998 (MacNeil et al., 2012). Severe laboratory-acquired infections have occurred with Flexal virus (FLEV), JUNV, LASV, LCMV, MACV, and SBAV (Milzer and Levinson 1942, Rugiero et al., 1962, Leifer et al., 1970, Vasconcelos et al., 1993, Gaidamovich et al., 2000). Mild and asymptomatic human infections with PICHV have also been reported (Gonzalez et al., 2007, Buchmeier et al., 1974)

LCMV acquired from house mice has also caused a highly fatal hepatitis in various captive callitrichid primates, in particular marmosets and tamarins (Montali et al., 1993). Both virus and host factors contribute to the outcome of experimental mammarenavirus infection of laboratory animals including

In general, New World mammarenaviruses are pathogenic for suckling but not weaned laboratory mice, whereas the situation is reversed for the Old World mammarenaviruses LCMV and LASV (Golden et al., 2015).

A diverse range of mammalian cell lines are susceptible to mammarenavirus infection in vitro.

Mammarenaviruses primarily infect cells of the myeloid and reticuloendothelial lineages but also hepatocytes, lymphocytes, and other cells (Johnson 1965, Hensley et al., 2011, Maiztegui 1975, González et al., 1980). Receptors mediating host cell entry are mainly DAG1 for Old World mammarenaviruses (e.g., some strains of LCMV and LASV) and Clade C New World mammarenaviruses (Cao et al., 1998, Spiropoulou et al., 2002), neuropilin-2 (NRP2) for LUJV (Raaben et al., 2017), and TFRC for Clade B New World mammarenaviruses (e.g., GTOV, JUNV, MACV) (Radoshitzky et al., 2007); however, virus entry by some strains has been observed in the absence of or in addition to these receptors using alternative factors, such as AXL receptor tyrosine kinase (AXL), calcium voltage-gated channel subunit alpha1 S (CACNA1S), C-type lectin domain family 4 member G (CLEC4G), CD209, hepatitis A virus cellular receptor (HAVCR1), or TYRO3 protein tyrosine kinase (TYRO3) (Brouillette et al., 2018, Shimojima et al., 2012, Sarute and Ross 2020)


Antigenic cross-reactions based on cross-protection, neutralization of infectivity, complement-fixation, and indirect immunofluorescence tests have been widely reported and involve antigenic determinants located primarily on NP and GP (Buchmeier et al., 1980, Damonte et al., 1986, Gajdamovič et al., 1975, Rowe et al., 1970b, Sanchez et al., 1989, Wolff et al., 1978). In addition, antibodies against the mammarenaviruses LCMV NP and Machupo virus (MACV) react weakly with the NP of the reptarenavirus University of Helsinki virus 1 (UHV-1). Human and rabbit anti-MACV sera also recognize UHV-1 NP (Hetzel et al., 2013). The mammarenavirus GP1 protein is the major virus neutralization and protective antigen. Antibodies to NP and, variably, to other virus proteins are also induced by infection but generally do not neutralize infectivity in vitro. Major complement-fixing antigens are associated with NP. Furthermore, NP and GP of LCMV and LASV contain cytotoxic T cell epitopes.

Mammarenaviruses have been divided into two groups based on antigenic properties. Old World mammarenaviruses (“Lassa–lymphocytic choriomeningitis serocomplex”) include viruses indigenous to Africa and the ubiquitous LCMV, whereas New World mammarenaviruses (“Tacaribe serocomplex”) include viruses indigenous to the Americas. New World mammarenaviruses are further subdivided into Clades A‒C based on NP sequences (Burri et al., 2013, Emonet et al., 2006, Gonzalez et al., 1986). This classification is largely congruent with phylogenetic data and mammarenavirus muroid rodent host phylogeny, with Old World mammarenaviruses infecting murid rodents (members of the family Muridae) primarily in Africa, and New World mammarenaviruses infecting cricetid rodents (members of the family Cricetidae) primarily in the Americas. However, this clear-cut dichotomy is under review, since yet-unclassified mammarenaviruses have been discovered in northern three-toed jerboas (Dipodoidea: Dipodidae: Dipus sagitta (Pallas, 1773)) in Mongolia (Wu et al., 2018)

Derivation of names

Mamm: from the Latin mamma, “udder or “breast”, referring to mammalian hosts of these viruses.  

Species demarcation criteria

The parameters used to assign viruses to different species in the genus are:

  • virus shares less than 80% nucleotide sequence identity in the S segment and less than 76% identity in the L segment;
  • association of the virus with a distinct main host or a group of sympatric hosts;
  • dispersion of the virus in a distinct defined geographical area;
  • association (or not) with human disease;
  • virus shares less than 88% NP amino acid sequence identity (Radoshitzky et al., 2015)

Relationships within the genus 

Phylogenetic relationships across the genus have been established from maximum likelihood trees generated from full or partial sequences of NP and L proteins (Figure 3.Mammarenavirus).

Figure 3A.MammarenavirusMaximum likelihood phylogenetic trees inferred from PRANK alignments (Löytynoja and Goldman 2008) of the NP (A - above) and L (B - below) amino acid sequences. For both alignments, the best-fit model of protein evolution (LG+G) was selected using ProtTest 3 (v. 3.4.2) (Darriba et al., 2011). Maximum likelihood trees with 1,000 bootstrap replicates were produced using RAxML (v. 8) (Stamatakis 2014). The percentage of replicate trees in which the associated taxa clustered together in the bootstrap is shown next to branch nodes (when ≥ 70%). The mid-point rooted trees were visualized using FigTree ( For NP, sequences of 45 mammarenaviruses assigned to 39 species (red) and 10 unclassified mammarenaviruses (white) were included. For L, the phylogeny includes sequences of 44 mammarenaviruses assigned to 39 species (red dots) and 9 unclassified mammarenaviruses (white dots). In both trees, representative viruses of the genera Hartmanivirus and Reptarenavirus are also included (green and yellow dots). Viruses belonging to the Old World and New World complexes are indicated by background shading of red or green respectively. These phylogenetic trees and corresponding sequence alignment are available to download from the Resources page.


Figure 3B.MammarenavirusMaximum likelihood phylogenetic trees inferred from PRANK alignments (Löytynoja and Goldman 2008) of the L amino acid sequences; see the above Figure 3A.Mammarenavirus legend for full details.

Member species

The Member Species table enumerating important virus exemplars classified under each species of the genus is provided at the bottom of the page.

Related, unclassified viruses

Virus name

Accession number

Virus abbreviation

Aporé virus

S segment: MF317490
L segment: MF317491


arenavirus 96010025

S segment: EU486820
L segment: not available


arenavirus DX1401

S segment: KJ144198*; 
L segment: KJ144197*


arenavirus Lemniscomys/F4-8/TZA/2008

S segment: not available; 
L segment: GU182412*


arenavirus Mus/TZ22285/TZA/2008

S segment: not available; 
L segment: GU182413*


arenavirus sp. 9408800235/ZAF

S segment: FJ383127*; 
L segment: not available


Black Mesa virus

S segment: FJ032026+FJ032027*; 
L: EU938670*


Bobomene virus

S segment: KF926408*; 
L segment: not available


Gbagroube virus

S segment: GU830848*; 
L segment: GU830849*


jerboa arenavirus

S segment: not available; 
L segment: MF642354*


Jirandogo virus

S segment: JX845169*; 
L segment: JX845167*


Kodoko virus

S segment: EF189586*; 
L segment: EF179864*


Lìjiāng virus

S segment: MF414202
L segment: MF414201


Menékré virus

S segment: GU830857*; 
L segment: GU830858*


Middle Pease River virus

S segment: JX657695*; 
L segment: not available


Natorduori virus

S segment: JX845170*; 
L segment: JX845168*


North American arenavirus 96010024

S segment: EU123331
L segment: not available


North American arenavirus 96010151

S segment: EU123330
L segment: not available


North American arenavirus D1240007

S segment: EU123329
L segment: not available


Ocozocoautla de Espinosa virus

S segment: JN897398
L segment: not available


Omdraaivlei virus

S segment: KF926410*; 
L segment: not available


Orogrande virus

S segment: EU910959*; 
L segment: EU938669*


Palo Verde virus (Milazzo et al., 2015)

Not available


Patawa virus

S segment: KJ668824*; 
L segment: KJ668825*


Pinhal virus

S segment: EU280547*; 
L segment: not available


Pistillo virus (Wildy 1971)

Not available


Real de Catorce virus

S segment: not available; 
L segment: JF430461*


Witsand virus

S segment: KF926412
L segment: not available


Xapuri virus

S segment: MG976578
L segment: MG976577


Virus names and virus abbreviations are not official ICTV designations.