Arenavirus

Mammarenavirus structure and genome composition.

Viewed in cross-section, arenaviruses contain grainy particles that are ribosomes acquired from their host cells. It is from this characteristic that they acquired the name arena, from the Latin root meaning sand. The ribosomal structures are not believed to be essential for virus replication. Virus particles, or virions, are pleomorphic (variable in shape) but are often spherical, with a diameter of 60–300 nm, and are covered with surface glycoprotein spikes.[4]

The virus contains a beaded nucleocapsid with two single-stranded RNA segments. The nucleocapsid consists of a core of nucleic acid enclosed in a protein coat. Although they are categorized as negative-sense viruses,[5] arenaviruses are ambisense. While sections of their genome encode genes in the negative sense (reverse polarity), other sections encode genes in the opposite (forward/positive sense) direction. This complex gene expression structure is theorized to be a primitive regulatory system, allowing the virus to control what proteins are synthesized at what point in the life cycle. The life cycle of the arenavirus is restricted to the cell cytoplasm.

Genomes of Arenaviridae

Arenaviruses have a segmented RNA genome that consists of two single-stranded ambisense RNAs.[6] As with all negative-sense RNA viruses, the genomic RNA alone is not infectious and the viral replication machinery is required to initiate infection within a host cell.[7] Genomic sense RNA packaged into the arenavirus virion is designated negative-sense RNA, and must first be copied into a positive-sense mRNA in order to produce viral protein.[8] The two RNA segments are denoted Small (S) and Large (L),[6][9] and code for four viral proteins in a unique ambisense coding strategy.[10][11] Each RNA segment codes for two viral proteins in opposite orientation such that the negative-sense RNA genome serves as the template for transcription of a single mRNA and the positive-sense copy of the RNA genome templates a second mRNA.[8] The separate coding sequences of the two viral proteins are divided by an intergenic region RNA sequence that is predicted to fold into a stable hairpin structure.[12]

The extreme termini of each RNA segment contains a 19 nucleotide highly conserved sequence that is critical for recruitment of the viral replication machinery and initiation of viral mRNA transcription and genomic replication.[13][14][15][16][17] The conserved 5' and 3' RNA termini sequences are complementary and allows each RNA segment to adopt a double-stranded RNA panhandle structure[18] that maintains the termini in close proximity and results in a circular appearance to purified arenavirus genomic templates visualized by electron microscopy.[19][20] The double-stranded RNA panhandle structure is critical for efficient viral RNA synthesis,[16][21] but potential interterminal double-stranded RNA interactions must be transiently relieved in order to recruit the viral polymerase.[17]

The S-segment RNA is approximately 3.5 kb, and encodes the viral nucleocapsid protein (NP) and glycoprotein (GPC).[22] The L-segment RNA is approximately 7.2 kb, and encodes the viral RNA-dependent RNA-polymerase (L) and a small RING-domain containing protein (Z).[23][24][25]

The Z protein forms homo oligomers and a structural component of the virions.[26] The formation of these oligomers is an essential step for particle assembly and budding. Binding between Z and the viral envelope glycoprotein complex is required for virion infectivity. Z also interacts with the L and NP proteins. Polymerase activity appears to be modulated by the association between the L and Z proteins. Interaction between the Z and NP proteins is critical for genome packaging.

Arenavirus replication cycle.

The glycoprotein (GP) is synthesised as a precursor molecule.[27] It is cleaved into three parts - GP1, GP2 and a stable signal peptide (SSP). These reactions are catalysed by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P). These processes are essential for fusion competence and incorporation of mature GP into nascent budding virion particles.

Within the family Arenaviridae, arenaviruses were formerly all placed in the genus Arenavirus, but in 2014 were divided into the genera Mammarenavirus for those with mammalian hosts and Reptarenavirus for those infecting snakes.[28][29] Reptarenaviruses and mammarenavirus are separated by an impenetrable species barrier. Infected rodents cannot pass disease onto snakes, and IBD in captive snakes is not transmissible to humans.

A third genus, Hartmanivirus (not to be confused with genus Haartmanvirus of vibrio phages in family Demerecviridae, order Caudovirales), has also been established,[30] including other species that infect snakes. The organisation of the genome of this genus is typical of arenaviruses but their glycoproteins resemble those of filoviruses. Species in this genus lack the matrix protein.

A fourth genus, Antennavirus has also been established[31] to accommodate two arenaviruses found in striated frogfish (Antennarius striatus).[32]

Mammarenaviruses can be divided into two serogroups, which differ genetically and by geographical distribution:[33] When the virus is classified "Old World" this means it was found in the Eastern Hemisphere in places such as Europe, Asia, and Africa. When it is found in the Western Hemisphere, in places such as Argentina, Bolivia, Venezuela, Brazil, and the United States, it is classified "New World". Lymphocytic choriomeningitis (LCM) virus is the only arenavirus to exist in both areas but is classified as an Old World virus. Old and New World area viruses appear to have diverged ~45,000 years ago.[34] The Old World Mammarenaviruses originated ~23.1-1.88 thousand years ago, most likely in Southern Africa while the New World Mammarenaviruses evolved in the Latin America-Caribbean region ~41.4-3.3 thousand years ago.

Old World complex

Arenavirus taxonomy and location

• Alxa virus (ALXV)
• Dandenong virus (DANV)
• Gairo virus (GAIV)
• Gbagroube virus
• Ippy virus (IPPYV)
• Kodoko virus (KODV)
• Lassa virus (LASV)
• Lìjiāng virus (LIJV)
• Loei River virus (LORV)
• Lujo virus(LUJV)
• Luna virus (LUAV)
• Lunk virus (LNKV)
• Lymphocytic choriomeningitis virus (LCMV)
• Mariental virus (MRTV)
• Merino Walk virus (MRWV)
• Menekre virus
• Minu virus
• Mobala virus (MOBV)
• Morogoro virus (MORV)
• Mopeia virus (MOPV)
• Ryukyu virus (RYKV)
• Solwezi virus (SOLV)
• Souris virus (SOUV)
• Okahandja virus (OKAV)
• Wenzhou virus (WENV)

The evolution of the Mammarenavirus genus has been studied.[34] The New World and Old World species diverged less than 45,000 years ago. The New World species evolved between 41,400 and 3,300 years ago in the Latin America-Caribbean region. The Old World species evolved between 23,100 and 1,880 years ago, most likely in southern Africa.

Some arenaviruses are zoonotic pathogens and are generally associated with rodent—transmitted disease in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenaviruses persist in nature by infecting rodents first and then transmitted into humans. Humans can be infected through mucosal exposure to aerosols, or by direct contact of abraded skin with the infectious material, derived from infected rodents.[4] Aerosols are fine mists or sprays of rodent dried excreta, especially urine that is dropped in the environment. Most of the Arenaviruses caught by humans are within their own homes when these rodents seek shelter. The virus can be caught in factories, from food that has been contaminated, or within agricultural work areas. Humans' risk of contracting the Arenavirus infection is related to age, race, or sex within the degree of contact with the dried rodent excreta.

Very few treatment methods are available. The current lack of a licensed vaccine and limited therapeutic options for the arenavirus make it arguably among the most neglected virus groups. The only licensed drug for the treatment of human arenavirus infection is the nucleoside analogue ribavirin.[40] Ribavirin reduces morbidity and mortality in humans infected with certain arenaviruses, such as LASV and JUNV infections, if it is taken in the early stages of the disease. Ribavirin displays mixed success in treating severe arenaviral disease and is associated with significant toxicities.[41]

• ICTV Report: Arenaviridae
• Viralzone: Arenavirus
• Virus Pathogen Database and Analysis Resource (ViPR): Arenaviridae
• Detailed genomic and bioinformatic information about Arenaviridae at NIH-funded database.
• Arenaviridae Genomes Archived 5 April 2017 at the Wayback Machine database search results from the Viral Bioinformatics Resource Center.
• Google.Org blog info on recent outbreak.
• Arenaviruses
• "Arenavirus". NCBI Taxonomy Browser. 11618.