Genus Alphavirus

Type Species	Sindbis virus	(SINV)

Distinguishing Features

Genomes are 11-12  kb in size (exclusive of the 3 terminal poly (A) tract: Sindbis virus (SINV), 11,703  nts; O’nyong-nyong virus (ONNV), 11,835  nts; RRV, 11,851  nts; VEEV, 11,444  nts; Semliki Forest virus (SFV) 11,442  nts; S_20w about 49). The order of the genes for the non-structural proteins in the genomic RNA is (Fig. 2) nsP1, nsP2, nsP3, nsP4. These are made as polyprotein precursors and processed by the nsP2 protease (Fig. 3). The gene order in the 26S mRNA is CP-E3-E2-6K-E1. The derived polyprotein is processed by an auto-proteolytic activity in the CP, by cellular signal peptidase, and by an enzyme thought to be a component of the Golgi apparatus (Fig. 3). Glycoprotein E2 is produced as a precursor, PE2 (otherwise called p62), that is cleaved during virus maturation. For some viruses the N-terminal cleavage product of PE2, referred to as E3 ( 10 10³), remains associated with the virion. Carbohydrates comprise about 14% of the mass of the envelope glycoproteins and about 5% of the mass of the alphavirus virion.

Alphaviruses possess the ability to replicate in and be transmitted horizontally by mosquitoes. Each virus usually has a preferred mosquito vector; however, as a group these viruses use a wide range of mosquitoes. Fort Morgan virus (FMV) is transmitted by arthropods of the family Cimicidae (Order Hemiptera) associated with birds. Most alphaviruses can infect a wide range of vertebrates. Many alphaviruses have different species of birds as their primary vertebrate reservoir host, but most are able to replicate in mammals as well. A number of alphaviruses have mammals as their primary vertebrate reservoir host. Some of these, such as Ross River virus (RRV), replicate poorly in birds. Alphavirus isolations from reptiles and amphibians have been reported. As a group, the viruses are found on all continents except Antarctica and on many islands. However, most viruses have a more limited distribution. Sindbis virus (SINV), the type species virus, has been isolated from many regions of Europe, Africa, Asia, the Philippines and Australia. WEEV is distributed discontinuously from Canada to Argentina. At the other extreme, ONNV has been isolated only from East Africa where it caused epidemics in the years 1959-60 and 1996-97. Many Old World alphaviruses cause serious, but not life threatening illnesses that are characterized by fever, rash and a painful arthralgia. RRV, Mayaro virus (MAYV), and the Ockelbo subtype of SINV cause epidemic polyarthritis in humans with symptoms (in a minority of cases) that may persist for months, or years. The New World alphaviruses, EEEV, VEEV and WEEV, regularly cause fatal encephalitis in humans, although the fraction of infections that lead to clinical disease is small. EEEV, WEEV, and VEEV also cause encephalitis in horses, and EEEV causes encephalitis in pheasants and emus. Highlands J virus (HJV) is generally not believed to be pathogenic for humans or horses, but is recognized as an important pathogen of turkeys, pheasants, chukar partridges, ducks, emus, and whooping cranes.

List of Species Demarcation Criteria in the Genus

The only formal parameters for alphavirus species delineation were adopted by the Subcommittee on Inter-Relationships Among Catalogued Arboviruses (SIRACA) of the American Committee on Arthropod-borne Viruses. This classification relied on antigenic data, and defined viruses or species as “individual agents, antigenically related but easily separable (four-fold or greater differences between the homologous and heterologous titers of both sera)”. Above the species level, antigenic complexes comprise “arboviruses that are very closely related but distinct from each other”. Below the species level, antigenic serotypes are “virus isolates separable from each other by at least a four-fold difference between the homologous and heterologous titers of one but not both of the two sera tested”, and antigenic varieties are “isolates differentiable only by the application of special tests or reagents (kinetic HI, monoclonal antibody assays, etc.)”.

With the increased genetic and ecological data now available, lineage divergence and ecological niche differentiation, species demarcation criteria adopted by the ICTV, can be combined with the SIRACA antigenic classification system to provide a more comprehensive approach to alphavirus classification. In general, results of phylogenetic studies have been consistent with antigenic relationships among alphaviruses. Viruses previously defined by the ICTV as species generally differ by more than 23% at the nucleotide level and 10% in amino acid sequences when E1 protein genes are compared (Fig. 4), and have distinct transmission cycles.

However, several exceptions exist:

1.

Ockelbo, Kyzylagach, and Babanki viruses do not represent lineages very distinct from Sindbis virus (they differ by less than 17% in nucleotide and 4% in amino acid sequences), are not ecologically distinct, and are considered serotypes by SIRACA. They are therefore clasified as serotypes of Sindbis virus.

2.

Everglades virus, Mucambo virus, Cabassou virus and Pixuna virus are considered by SIRACA to be serotypes of VEEV. With the exception of Everglades virus, which is not distinct genetically from VEEV, these viruses represent very distinct lineages (they differ from VEEV by 26% in nucleotide sequences and 14-18% in amino acids). All including Everglades virus have important differences in their natural host relationships and distribution. They are therefore considered distinct species within the VEEV complex. Strain Ag80-663, another member of the VEEV antigenic complex, is also relatively distinct genetically from VEEV (32% nucleotide and 26% amino acid sequence divergence in the PE2 gene) and is probably distinct ecologically, qualifying it as a distinct species. Ross River virus (RRV) is considered a serotype of Getah virus (GETV) (24% nucleotide, 14% amino acid sequence divergence), O’nyong-nyong virus (ONNV) a serotype of Chikungunya virus (CHIKV) (23% nucleotide, 14% amino acid sequence divergence), and Una virus (UNAV) a serotype of Mayaro virus (MAYV) (33% nucleotide, 27% amino acid sequence divergence) by SIRACA. With the exception of MAYV and UNAV, these lineage divergence values are consistent with the maximum values of other alphaviruses considered synonymous. However, CHIKV and ONNV have important ecological differences (especially vector associations) and are therefore retained as distinct species.

List of Species in the Genus

Official virus species names are in italics. Tentative virus species names, alternative names ( ), strains or serotypes are not italicized. Virus names, genome sequence accession numbers [ ], and assigned abbreviations ( ) are:

Species in the Genus

Ag80-663 virus	[AF075258, U94610]	(AG80V)
Aura virus	[S78478]	(AURAV)
Barmah Forest virus	[U73745]	(BFV)
Bebaru virus	[U94595]	(BEBV)
Cabassou virus	[AF075259, U94611]	(CABV)
Chikungunya virus	[L37661, U94597]	(CHIKV)
Eastern equine encephalitis virus	[D01034]	(EEEV)
Everglades virus	[AF075251, U94608]	(EVEV)
Fort Morgan virus	[U60399,U60404]	(FMV)
Buggy Creek virus	[U94607, U60403, U60395]
Getah virus	[U94568]	(GETV)
Highlands J virus	[J02206,U60401, U94609]	(HJV)
Mayaro virus	[U94602]	(MAYV)
Middelburg virus	[J02246, U94599]	(MIDV)
Mucambo virus	[AF075253, U94615]	(MUCV)
Tonate	[AF075254]
Ndumu virus	[U94600]	(NDUV)
O’nyong-nyong virus	[M33999]	(ONNV)
Pixuna virus	[AF075256, U94613]	(PIXV)
Ross River virus	[M20162]	(RRV)
Sagiyama virus	[U94601]
Semliki Forest virus	[X04129]	(SFV)
Sindbis virus	[V00073]	(SINV)
Babanki	[U94604, U60394, U60400]
Kyzylagach	[U94605, U60396, U60402]
Ockelbo	[M69205]
Una virus	[U94603]	(UNAV)
Venezuelan equine encephalitis virus	[X04368]	(VEEV)
Western equine encephalitis virus	[J03854, U01065, AF109297]	(WEEV)
Whataroa virus	[U94606, U60398, U60408]	(WHAV)

Tentative Species in the Genus

None reported.