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The flaviviruses are a family of small enveloped viruses with positive-strand RNA genomes of approximately 9.0 to13 kbp. Most infect mammals and birds. Many flaviviruses are host-specific and pathogenic, such as hepatitis C virus (HCV) in the genus, Hepacivirus. The majority of known members in the genus Flavivirus are arthropod borne, many of which are important human and veterinary pathogens (e.g., yellow fever virus, dengue virus, West Nile virus).
Table 1. Flaviviridae. Characteristics of the family Flaviviridae
yellow fever virus-17D (X03700), species Yellow fever virus, genus Flavivirus
Enveloped, 40–60 nm virions with a single core protein (except for genus Pegivirus) and 2 or 3 envelope glycoproteins
Approximately 9.0–13 kb of positive-sense, non-segmented RNA
Cytoplasmic, in membrane vesicles derived from the endoplasmic reticulum (ER); assembled virions bud into the lumen of the ER and are secreted through the vesicle transport pathway
Directly from genomic RNA containing a type I cap (genus Flavivirus) or an internal ribosome entry site (other genera)
Mammals (all genera); most members of genus Flavivirus are arthropod borne
Currently four genera containing more than 60 species
Flavivirus. This genus consists primarily of >50 species of arthropod-borne viruses, with distinct groups infecting mosquitoes or ticks. Mammals and birds are the usual primary hosts, in which infections range from asymptomatic to severe or fatal haemorrhagic fever or neurological disease. Important human pathogens include yellow fever virus, dengue virus, Zika virus, Japanese encephalitis virus, West Nile virus and tick-borne encephalitis virus. Other members cause economically important diseases in domestic or wild animals. Additional viruses infecting only arthropods or only mammals (e.g., Tamana bat virus) have been described recently.
Pestivirus. These viruses infect pigs and ruminants, including cattle, sheep, goats and wild ruminants, and are transmitted through contact with infected secretions (respiratory droplets, urine or faeces). Infections may be subclinical or cause enteric, haemorrhagic or wasting diseases, including the economically important bovine viral diarrhoea virus and classical swine fever virus. Additional pestiviruses of unknown pathogenicity that infect bats and rats have been identified recently.
Hepacivirus. This genus includes HCV, a major human pathogen causing chronic liver disease, including cirrhosis and cancer, and several other viruses of unknown pathogenicity that infect horses, rodents, bats, cows and primates. Infections are typically persistent and target the liver.
Pegivirus. Members are widely distributed in a range of mammalian species, in which they cause persistent infections. To date they have not been clearly associated with disease.
Virions are 40-60nm in diameter, spherical in shape with a lipid envelope. The capsid is comprised of a single protein and the envelope contains two or three virus-encoded membrane proteins. Specific descriptions of the four individual genera are given in the corresponding sections.
The virion Mr, buoyant density, sedimentation coefficient and other physicochemical properties differ among the members of the genera and are described separately in the corresponding sections.
Genomes are positive-sense ssRNA of approximately 9.2-11.0, 11.5-13.0, 8.9-10.5 and 8.9-11.3 kb for members of the genera Flavivirus, Pestivirus, Hepacivirus and Pegivirus, respectively. All members of the family lack a 3′-terminal poly(A) tract. Only the genomes of members of the genus Flavivirus contain a 5′-terminal type I cap structure, the others possess an internal ribosomal entry site (IRES).
Virions of members of the family have a single, small basic capsid (C) and two (Flavivirus, Hepacivirus and Pegivirus) or three (Pestivirus) membrane-associated envelope proteins. Pegiviruses appear to lack a complete nucleocapsid protein gene. The nonstructural proteins contain sequence motifs characteristic of a serine protease, RNA helicase and RNA dependent RNA polymerase (RdRp) that are encoded at similar locations along the genome in all genera. Further details of specific functional properties are given in the corresponding sections of the individual genera.
Lipids present in virions are derived from host cell membranes and make up 17% of the total virion weight in the case of members of the genus Flavivirus. The lipid content of pesti- hepaci-, and pegiviruses has not been determined.
Virions contain carbohydrates in the form of glycolipids and glycoproteins.
The genomic RNA of all members of the family has a similar organization and is the viral mRNA found in infected cells. It contains a single long open reading frame (ORF) flanked by 5′- and 3′-terminal non-coding regions (NCRs) that form specific secondary structures required for genome replication and translation. Members of the genus Flavivirus, but not pestiviruses, hepaciviruses or pegiviruses produce a unique, subgenomic, small (0.3–0.5 kb) non-coding RNA that is derived from the 3′-NCR of genomic RNA (Lin et al., 2004) but which is essential for virus replication in cells and modulates pathogenicity in animals. Translation-initiation of genomic RNA is cap-dependent for members of the genus Flavivirus, whereas IRES elements are present in viruses of the other genera. Viral proteins are synthesized as part of a polyprotein that is co- and post-translationally cleaved by viral and cellular proteases. The structural proteins are contained in the N-proximal portion of this polyprotein and the nonstructural proteins in the remainder. The latter include a serine protease, an RNA helicase and the RdRp. Genome replication occurs in the cytoplasm in association with modified cellular membranes via the synthesis of genome-length negative-strand intermediates. Virion assembly, including acquisition of a glycoprotein-containing lipid envelope, occurs by budding through intracellular membranes. Viral particles are transported in cytoplasmic vesicles through the secretory pathway before they are released by exocytosis, as shown for members of the genus Flavivirus and assumed for members of the other genera. In addition, release of infectious RNA via exosomes has recently been demonstrated (Ramakrishnaiah et al., 2013).
The viruses of different genera are antigenically unrelated, but serological cross-reactivity exists among members within each genus.
The biological properties of viruses in the four genera exhibit different characteristics and are described in the corresponding sections.
Flavi: from Latin flavus, “yellow”.
Pesti: from Latin pestis, “plague”.
Hepaci: from Greek hepar, hepatos, “liver”.
Pegi: from “Pe” for persistent, and “G” for original names of GB viruses and hepatitis G.
Phylogenetic relationships of amino acid sequences in a conserved domain of the RdRp show clustering of members of the Flaviviridae into the four currently assigned genera, although there is a closer phylogenetic relationship between members of the Hepacivirus and Pegivirus genera than between others (Figure 1.Flaviviridae). Another exception is the outlier position of Tamana bat virus, currently listed as a potential member of the Flavivirus genus, but sufficiently distinct to potentially merit assignment into a new genus, should further related viruses be found in the future.
Figure 1.Flaviviridae. Phylogeny of conserved amino acid sequences in the RdRp (NS5 or NS5B) of the family Flaviviridae. Partial gene sequences between positions 8040–8897 (numbered using positions in the HCV sequence, AF011751) were taken from the representative strains listed in the MSL and related unclassified viruses listed in the chapter. MUSCLE (Edgar, 2004) was used to create a multiple alignment for the aa sequences which was then verified by alignment of the known motifs in the region. An unrooted phylogenetic tree was constructed from the sequence alignment by The tree constructed by maximum likelihood using an empirically determined optimal substitution model – Le Gascuel 2008 with a gamma distribution (5 categories) and invariant sites (LG + G+I) computed with the MEGA version 6.1 package (Tamura et al., 2013). Data was bootstrap re-sampled 100 times; values of >=70% are shown next to the branches.
Members of the Flaviviridae have been placed into RNA virus supergroup II, a group that also includes the Tombusviridae (plant), members of the Luteovirus genus in the Luteoviridae (plant), Leviviridae (bacterial virus) and a series of recently described insect-derived flavi-like viruses, many with segmented genomes (Shi et al., 2015). However, the virion structure and other viral structural and nonstructural genes in these other virus groups are distinct and likely non-homologous.
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