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The flaviviruses are a family of small enveloped viruses with RNA genomes of 9000-12,000 bases in length. Most infect mammals and birds, many of which are host-specific and pathogenic, such as hepatitis C virus (HCV) in the genus, Hepacivirus. The majority of known members in one genus (Flavivirus) are arthropod borne, many of which are important human and veterinary pathogens (eg. yellow fever virus, dengue virus).
Table 1. Characteristics of family Flaviviridae.
Yellow fever virus (X03700), genus Flavivirus
9–11 kb of positive-sense, non-segmented RNA
Enveloped, 40-60 nm virions with a single core protein (except for genus Pegivirus) and 2-3 envelope glycoproteins
Directly from genomic RNA containing a type I cap or an internal ribosomal entry site (IRES)
Mammals (all genera); most members of genus Flavivirus are arthropod-borne
Currently 4 genera containing more than 60 species
Viruses classified into the four genera show distinct host ranges and modes of transmission:
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 may be asymptomatic or cause severe or fatal haemorrhagic fever or neurological disease. Important human pathogens include yellow fever virus, Dengue virus, Japanese encephalitis virus, West Nile virus and tick-borne encephalitis virus. Other members cause economically important diseases in domestic or wild animals. Additional species 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.
Hepacivirus. This genus includes HCV, a major human pathogen causing progressive liver disease, and also 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.
Flavivirus virions are 40–60 nm in diameter, spherical in shape and contain a lipid envelope. The capsid is composed 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, 12.3-13.00, 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 member of the genus Flavivirus contain a 5′-terminal type I cap structure, the other possess internal ribosomal entry sites (IRESs).
The 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 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 flaviviruses. 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 ORF flanked by 5′- and 3′-terminal non-coding regions (NCRs) that form specific secondary structures required for genome replication and translation. Flaviviruses, but not pestiviruses, hepaciviruses or pegiviruses produce a unique, subgenomic, small (0.3–0.5 kb) non-coding RNA derived from 3′-NCR of genomic RNA, which is essential for virus replication in cells and modulates pathogenicity in animals. Translation-initiation of genomic RNA is cap-dependent in the case of flaviviruses, whereas IRES elements are present in 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-terminal portion of this polyprotein and the non-structural proteins in the remainder. The latter include a serine protease, an RNA helicase and the RdRp. RNA synthesis occurs in the cytoplasm in association with modified cellular membranes via synthesis of full-length negative-strand intermediates. Some flaviviruses appear to harbour sequences that induce a proportion of translating ribosomes to shift-1 nt and continue translating in the new reading frame to produce a 'transframe' fusion protein. When functionally utilized, this is referred to as programmed-1 ribosomal frameshifting (-1 PRF). In the case of the Japanese encephalitis virus serogroup, frameshifting results in the production of a C-terminally extended version of NS1 known as NS1'. 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.
The genera are antigenically unrelated, but serological cross-reactivity exists among members within each genus.
The biological properties of the four genera exhibit different characteristics and are described in the corresponding sections.
Figure 1. Phylogeny of the RdRp of hepaciviruses and pegiviruses. The tree was constructed maximum likelihood phylogenetic analysis of available complete genome sequences of hepaciviruses and pegiviruses infecting different mammalian species (see Key legend). Phylogenetic analysis of each dataset used 100 bootstrap re-samplings to determine robustness of grouping, values shown on branches. Abbreviations: HcV: hepacivirus; PgV:pegivirus; OWM: old world monkey; NWM: New world monkey; R: rodent; B: bat; Bo: bovine; NPHV: non-primate hepacivirus. Pegiviruses in Group 2 possess the additional X and Y predicted structural proteins and a type IV IRES. This figure was modified from Kapoor et al., (PMC4600124).
Figure 2. Phylogeny of the conserved sequences in the RdRp (NS5 or NS5B) of classified members of the family Flaviviridae. Partial gene sequences (292 aa, positions 7704–8550 numbered as in the HCV-1 genome, AF011751) from the representative strains listed in each table. CLUSTALW was used to create a multiple alignment for the aa sequences which was verified by alignment of the known motifs in the region. An unrooted phylogenetic tree was constructed from the sequence alignment by neighbor-joining of (uncorrected) amino acid p-distances using the MEGA version 4.1 package. The virus names corresponding to the abbreviations can be found in the “List of species” in each genus. Note that the Entebbe virus group comprising Entebbe bat virus, Sokoluk virus and Yokose virus have no known vector but group phylogenetically within the mosquito-borne flaviviruses. Nounané, Chaoyang, Ngoye and Lammi viruses are not currently assigned to a specific virus group but also group within the mosquito-borne viruses.
Members of the Flaviviridae have been classified into RNA virus supergroup II, a group that also includes the Tombusviridae (plant), Luteoviridae (plant) Umbravirus (plant) and Leviviridae (phage). However, virion structure and other viral structural and nonstructural genes are distinct and likely non-homologous.
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.