# Flaviviridae

Flaviviridae is a family of enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vectors (mainly ticks and mosquitoes). The family gets its name from the yellow fever virus; flavus is Latin for "yellow", and yellow fever in turn was named because of its propensity to cause jaundice in victims. There are 89 species in the family divided among four genera. Diseases associated with the group include: hepatitis (hepaciviruses), hemorrhagic syndromes, fatal mucosal disease (pestiviruses), hemorrhagic fever, encephalitis, and the birth defect microcephaly (flaviviruses).

## Structure

Virus particles are enveloped and spherical with icosahedral-like geometries that have pseudo T=3 symmetry. They are about 40–60 nm in diameter.

## Genome

Members of the family Flaviviridae have monopartite, linear, single-stranded RNA genomes of positive polarity, and 9.6 to 12.3 kilobase in total length. The 5'-termini of flaviviruses carry a methylated nucleotide cap, while other members of this family are uncapped and encode an internal ribosome entry site.
The genome encodes a single polyprotein with multiple transmembrane domains that is cleaved, by both host and viral proteases, into structural and non-structural proteins. Among the non-structural protein products (NS), the locations and sequences of NS3 and NS5, which contain motifs essential for polyprotein processing and RNA replication respectively, are relatively well conserved across the family and may be useful for phylogenetic analysis.

## Life cycle

Viral replication is cytoplasmic. Entry into the host cell is achieved by attachment of the viral envelope protein E to host receptors, which mediates clathrin-mediated endocytosis. Replication follows the positive-stranded RNA virus replication model. Positive-stranded RNA virus transcription is the method of transcription. Translation takes place by viral initiation. The virion assembles by budding through intracellular membranes and exits the host cell by exocytosis.
| Genus | Host details | Tissue tropism | Entry details | Release details | Replication site | Assembly site | Transmission |
| Flavivirus | Humans; mammals; mosquitoes; ticks | Epithelium: skin; epithelium: kidney; epithelium: intestine; epithelium: testes | Clathrin-mediated endocytosis | Secretion | Cytoplasm | Cytoplasm | Zoonosis; arthropod bite |
| Hepacivirus | Humans | Epithelium: skin; epithelium: kidney; epithelium: intestine; epithelium: testes | Clathrin-mediated endocytosis | Secretion | Cytoplasm | Cytoplasm | Sex; blood |
| Pegivirus | Mammals | None | Clathrin-mediated endocytosis | Secretion | Cytoplasm | Cytoplasm | Unknown |
| Pestivirus | Mammals | None | Clathrin-mediated endocytosis | Secretion | Cytoplasm | Cytoplasm | Vertical: parental |

## Host range and evolutionary history

A wide variety of natural hosts are used by different members of the Flaviviridae, including fish, mammals including humans and various invertebrates, such as those specific to mollusks and crustaceans. The genomes of these flaviviruses show close synteny with that of the flavivirus type species, yellow fever virus. One flavivirus, the Wenzhou shark flavivirus, infects both Pacific spadenose sharks (Scoliodon macrorhynchos) and Gazami crabs (Portunus trituberculatus) with overlapping ranges, raising the possibility of a two-host marine lifecycle. However, another clade of flavivirus, the insect-specific flaviviruses, have genomes that do not demonstrate strong synteny with any of these groups, suggesting a complex evolutionary history.
Flavivirus endogenous viral elements, traces of flavivirus genomes integrated into the host's DNA, are found in many species, including a tadpole shrimp Lepidurus articus, the water flea Daphnia magna and a freshwater jellyfish Craspedacusta sowerbii, suggesting ancient coevolution between animal and flavivirus lineages. Many of the well-known members of the family causing disease in vertebrates are transmitted via arthropod vectors (ticks and mosquitoes).

## Taxonomy

The Flaviviridae are part of RNA virus supergroup II, which includes certain plant viruses and bacterial viruses.
The family has four genera:
* Genus Flavivirus, renamed Orthoflavivirus in 2023, (includes Dengue virus, Japanese encephalitis virus, Kyasanur Forest disease virus, Powassan virus, West Nile virus, Yellow fever virus, and Zika virus)
* Genus Hepacivirus (includes hepatitis C virus and GB virus B)
* Genus Pegivirus (includes GB virus A, GB virus C, and GB virus D))
* Genus Pestivirus (includes bovine viral diarrhea virus 1) and classical swine fever virus, previously hog cholera virus)). Viruses in this genus infect nonhuman mammals.

### Unclassified

Other Orthoflaviviruses are known that have yet to be classified. These include Wenling shark virus.
Jingmenvirus is a group of unclassified viruses in the family which includes Alongshan virus, Guaico Culex virus, Jingmen tick virus and Mogiana tick virus. These viruses have a segmented genome of four or five pieces. Two of these segments are derived from flaviviruses.
A number of viruses may be related to the flaviviruses, but have features that are atypical of the flaviviruses. These include citrus Jingmen-like virus, soybean cyst nematode virus 5, Toxocara canis larva agent, Wuhan cricket virus, and possibly Gentian Kobu-sho-associated virus.

## Clinical importance

Major diseases caused by members of the family Flaviviridae include:
* Dengue fever
* Hepatitis C
* Japanese encephalitis
* Kyasanur Forest disease
* Murray Valley encephalitis
* St. Louis encephalitis
* Tick-borne encephalitis
* West Nile encephalitis
* Yellow fever
* Zika fever