|
Type Species |
(YFV) |
Most flaviviruses are transmitted to vertebrate hosts by arthropod vectors, mosquitos or ticks, in which they actively replicate. Some flaviviruses are zoonotic agents transmitted between rodents or bats without known arthropod vectors.
Virions are approximately 50 nm in diameter and spherical in shape (Fig. 1). Two virus forms can be distinguished. Mature virions contain two virus encoded membrane-associated proteins, E and M. Intracellular, immature virions contain the precursor prM instead of M, which is proteolytically cleaved in the course of maturation. Detailed structural analyses have been carried out with Tick-borne encephalitis virus. Its major envelope protein E forms a dimer, the atomic structure of which has been determined by X-ray crystallography. The E protein dimer has a rod-like shape and is oriented parallel to the membrane, that is, it does not form a spike-like projection in its neutral-pH conformation. Image reconstructions from cryo-electron micrographs suggest that the virion envelope and the core have an icosahedral symmetry.
Physicochemical and Physical Properties
Virion Mr has not been precisely determined but can be estimated from the virus composition to be about 6 
107. Mature virions sediment at approximately 200S and have a buoyant density of approximately 1.19 g/cm3 in sucrose. Viruses are stable at slightly alkaline pH 8.0 but are readily inactivated at acidic pH, temperatures above 40°C, organic solvents, detergents, ultraviolet light and gamma-irradiation. With respect to inactivation procedures it has to be kept in mind that the virion RNA itself is infectious.
The genomes of flaviviruses are positive-sense ssRNA of approximately 11 kb. The 5
-end of the genome possesses a type I cap (m-7GpppAmp) followed by the conserved dinucleotide AG. The 3 ends lack a terminal poly(A) tract and terminate with the conserved dinucleotide CU. The sequences of flavivirus genomes are accessible from GenBank.
Virions contain three structural proteins: the capsid protein (C), the major envelope protein (E), and either prM (immature virions) or M (mature virions). The atomic structure of a soluble dimeric form of protein E has been determined by X-ray crystallography. The E protein is the viral hemagglutinin and is believed to mediate both receptor binding and acid pH-dependent fusion activity after uptake by receptor-mediated endocytosis. Seven nonstructural proteins are synthesized in infected cells: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. NS3 is a multi-functional protein. The N-terminal one-third of the protein forms the viral serine proteinase complex together with NS2B which is involved in the processing of the polyprotein. The C-terminal portion of NS3 contains an RNA helicase domain involved in RNA replication, as well as an RNA triphosphatase activity that is probably involved in the formation of the 5-terminal cap structure of the viral RNA. NS5 is the largest and most highly conserved flavivirus protein. NS5 is the flavivirus RNA-dependent RNA polymerase and also possesses motifs suggesting that it encodes the methyltransferase activity necessary for methylation of the 5-cap structure.
Virions contain about 17% lipid by weight; lipids are derived from host cell membranes.
Virions contain about 9% carbohydrate by weight (glycolipids, glycoproteins); their composition and structure are dependent on the host cell (vertebrate or arthropod). N-glycosylation sites are present in the proteins prM (1 to 3 sites), E (0 to 2 sites), and NS1 (1 to 3 sites).
Genome Organization and Replication
The genome RNA represents the only viral messenger RNA in flavivirus-infected cells. It consists of a single long ORF of more than 10,000 bases that codes for all structural and nonstructural proteins and is flanked by short NCRs at the 5- and 3-terminal ends (Fig. 2).
While nucleotide sequences are divergent, predicted secondary structures within the 5 and 3-NCRs are conserved among different flaviviruses. The NCRs do contain stretches of conserved RNA sequences that are distinct in mosquito- and tick-borne flaviviruses. The length of the 3-NCR of Tick-borne encephalitis virus can vary significantly, from 450 to almost 800 nts, and in some cases may contain an internal poly(A) tract. RNA synthesis appears to occur on the membranes of the perinuclear endoplasmic reticulum. After translation of the incoming genomic RNA, RNA replication begins with synthesis of complementary negative strands, which are then used as templates to produce additional genome-length positive-stranded molecules. These are synthesized by a semiconservative mechanism involving replicative intermediates (containing double-stranded regions as well as nascent single-stranded molecules) and replicative forms (duplex RNA molecules). Negative strand synthesis in flavivirus-infected cells continues throughout the replication cycle. Translation usually starts at the first AUG of the ORF but may also occur at a second in-frame AUG located 12 to 14 codons downstream in mosquito-borne flaviviruses. The polyprotein is processed by cellular proteases and the viral NS2B-NS3 serine protease to give rise to the mature structural and nonstructural proteins. Protein topology with respect to the ER and cytoplasm is determined by internal signal and stop-transfer sequences. Proliferation and hypertrophy of intracellular membranes is a characteristic feature of flavivirus-infected cells. The replication complex sediments with membranous fractions of infected cell extracts. Virus particles can first be observed in the rough endoplasmic reticulum, which is believed to be the site of virus assembly. These immature virions are then transported through the membrane systems of the host secretory pathway to the cell surface where exocytosis occurs. Shortly before virion release, the prM protein is cleaved by furin or a furin-like cellular protease to generate mature virions. Flavivirus-infected cells also release a noninfectious subviral particle that has a lower sedimentation coefficient than whole virus (70S vs. 200S) and exhibits hemagglutination activity (slowly sedimenting hemagglutinin; SHA).
All flaviviruses are serologically related, which can be demonstrated in binding assays such as ELISA and by hemagglutination-inhibition using polyclonal and monoclonal antibodies. Neutralization assays are more discriminating and have been used to define several serocomplexes of more closely related flaviviruses (see List of Species in the Genus). The envelope protein E is the major target for neutralizing antibodies and induces protective immunity. The E protein also induces flavivirus cross-reactive non-neutralizing antibodies. Antigenic sites involved in neutralization have been mapped to each of the three structural domains of the E protein. Antibodies to prM can also mediate immunity, probably by neutralizing viruses with partially uncleaved prM.
Flaviviruses can infect a variety of vertebrate species and in many cases arthropods. Some viruses have a limited vertebrate host range (e.g., only primates), others can infect and replicate in a wide variety of species (mammals, birds, etc.). Arthropods are usually infected when they feed on a vertebrate host during viremia, but non-viremic transmission has also been described for tick-borne flaviviruses.
Transmission and Vector Relationships
Most flaviviruses are arthropod-borne viruses that are maintained in nature by transmission from hematophagous arthropod vectors to vertebrate hosts. About 50% of known flaviviruses are mosquito-borne, 28% are tick-borne, and the rest are zoonotic agents transmitted between rodents or bats without known arthropod vectors. In some instances, the transmission cycle has not yet been identified. In the arthropod vectors, the viruses may also be passed on transovarially (mosquitoes, ticks) and transstadially (ticks).
Flaviviruses have a world-wide distribution but individual species are restricted to specific endemic or epidemic areas (e.g., Yellow fever virus (YFV) in tropical and subtropical regions of Africa and South America; Dengue virus in tropical areas of Asia, Oceania, Africa, Australia, and the Americas; Japanese encephalitis virus in South-East Asia; Tick-borne encephalitis virus in Europe and Northern Asia).
More than 50% of known flaviviruses have been associated with human disease, including the most important human pathogens YFV, Dengue virus (DENV) types 1 to 4, Japanese encephalitis virus (JEV), and TBEV. Flavivirus-induced diseases may be associated with symptoms of the central nervous system (e.g., meningitis, encephalitis), fever, arthralgia, rash, and hemorrhagic fever. Several flaviviruses are pathogenic for domestic or wild animals (turkey, pig, horse, sheep, dog, grouse, muskrat) and cause economically important diseases.
List of Species Demarcation Criteria in the Genus
The list of species demarcation criteria in the genus is:
|
Nucleotide and deduced amino acid sequence data, |
|
Antigenic characteristics, |
|
Geographic association, |
|
Vector association, |
|
Host association, |
|
Disease association, |
|
Ecological characteristics. |
Other defined members of individual species, which however do not constitute a species on their own, are shown below the species. Those viruses for which insufficient information is available are listed as ‘tentative’ within the group of viruses to which they are most closely related by sequence analysis.
Virus species in the Genus can be grouped serologically and in terms of their vector preferences as shown in the list provided.
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:
|
1-Tick-borne viruses | ||
|
Mammalian tick-borne virus group | ||
|
Gadgets Gully virus |
[AF013374] |
(GGYV) |
|
Kadam virus |
[AF013380] |
(KADV) |
|
Kyasanur Forest disease virus |
[X74111] |
(KFDV) |
|
Langat virus |
[M73835] |
(LGTV) |
|
Omsk hemorrhagic fever virus |
[X66694] |
(OHFV) |
|
Powassan virus |
[L06436] |
(POWV) |
|
Royal Farm virus |
[AF013398] |
(RFV) |
|
Karshi virus |
[AF013381] |
(KSIV) |
|
Tick-borne encephalitis virus |
(TBEV) | |
|
European subtype |
[M27157, M33668] |
|
|
Far Eastern subtype |
[X07755] |
|
|
Siberian subtype |
[L40361] |
|
|
Louping ill virus |
[Y07863] |
(LIV) |
|
Irish subtype |
[X86784] |
|
|
British subtype |
[D12937] |
|
|
Spanish subtype |
[X77470] |
|
|
Turkish subtype |
[X69125] |
|
|
Seabird tick-borne virus group | ||
|
Meaban virus |
[AF013386] |
(MEAV) |
|
Saumarez Reef virus |
[X80589] |
(SREV) |
|
Tyuleniy virus |
[X80588] |
(TYUV) |
|
2-Mosquito-borne viruses | ||
|
Aroa virus group | ||
|
Aroa virus |
[AF013362] |
(AROAV) |
|
Bussuquara virus |
[AF013366] |
(BSQV) |
|
Iguape virus |
[AF013375] |
(IGUV) |
|
Naranjal virus |
[AF013390] |
(NJLV) |
|
Dengue virus group | ||
|
Dengue virus |
(DENV) | |
|
Dengue virus type 1 |
[23027] |
(DENV-1) |
|
Dengue virus type 2 |
[M19197] |
(DENV-2) |
|
Dengue virus type 3 |
[A34774] |
(DENV-3) |
|
Dengue virus type 4 |
[M14931] |
(DENV-4) |
|
Kedougou virus |
[AF013382] |
(KEDV) |
|
Japanese encephalitis virus group | ||
|
Cacipacore virus |
[AF013367] |
(CPCV) |
|
Koutango virus |
[AF013384] |
(KOUV) |
|
Japanese encephalitis virus |
[M18370] |
(JEV) |
|
Murray Valley encephalitis virus |
[X03467] |
(MVEV) |
|
Alfuy virus |
[AF013360] |
(ALFV) |
|
St. Louis encephalitis virus |
[M1661] |
(SLEV) |
|
Usutu virus |
[AF013412] |
(USUV) |
|
West Nile virus |
[M12294] |
(WNV) |
|
Kunjin virus |
[D00246] |
(KUNV) |
|
Yaounde virus |
[AF013413] |
(YAOV) |
|
Kokobera virus group | ||
|
Kokobera virus |
[AF013383] |
(KOKV) |
|
Stratford virus |
[AF013407] |
(STRV) |
|
Ntaya virus group | ||
|
Bagaza virus |
[AF013363] |
(BAGV) |
|
Ilheus virus |
[AF013376] |
(ILHV) |
|
Rocio virus |
[AF013397] |
(ROCV) |
|
Israel turkey meningoencephalomyelitis virus |
[AF013377] |
(ITV) |
|
Ntaya virus |
[AF013392] |
(NTAV) |
|
Tembusu virus |
[AF013408] |
(TMUV) |
|
Spondweni virus group | ||
|
Zika virus |
[AF013415] |
(ZIKV) |
|
Spondweni virus |
[AF013406] |
(SPOV) |
|
Yellow fever virus group | ||
|
Banzi virus |
[L40951] |
(BANV) |
|
Bouboui virus |
[AF013364] |
(BOUV) |
|
Edge Hill virus |
[AF013372] |
(EHV) |
|
Jugra virus |
[AF013378] |
(JUGV) |
|
Saboya virus |
[AF013400] |
(SABV) |
|
Potiskum virus |
[AF013395] |
(POTV) |
|
Sepik virus |
[AF013404] |
(SEPV) |
|
Uganda S virus |
(UGSV) | |
|
Wesselsbron virus |
(WESSV) | |
|
Yellow fever virus |
[X03700] |
(YFV) |
|
3- viruses with no known arthropod vector |
||
|
Entebbe bat virus group | ||
|
Entebbe bat virus |
[AF013373] |
(ENTV) |
|
Sokoluk virus |
[AF013405] |
(SOKV) |
|
Yokose virus |
[AF013414] |
(YOKV) |
|
Modoc virus group | ||
|
Apoi virus |
[AF013361] |
(APOIV) |
|
Cowbone Ridge virus |
[AF013370] |
(CRV) |
|
Jutiapa virus |
[AF013379] |
(JUTV) |
|
Modoc virus |
[AF013387] |
(MODV) |
|
Sal Vieja virus |
[AF013401] |
(SVV) |
|
San Perlita virus |
[AF013402] |
(SPV) |
|
Rio Bravo virus group | ||
|
Bukalasa bat virus |
Bukalasa bat virus |
(BBV) |
|
Carey Island virus |
[AF013368] |
(CIV) |
|
Dakar bat virus |
[AF013371] |
(DBV) |
|
Montana myotis leukoencephalitis virus |
[AF013388] |
(MMLV) |
|
Phnom Penh bat virus |
[AF013394] |
(PPBV) |
|
Batu Cave virus |
[AF013369] |
(BCV) |
|
Rio Bravo virus |
[AF013396] |
(RBV) |
Tentative Species in the Genus
|
Tamana bat virus |
(TABV) | |
|
Cell fusing agent virus |
[M91671] |
(CFAV) |
|
|  |
