Flavivirus

See text Flavivirus, renamed Orthoflavivirus in 2023,[3] is a genus of positive-strand RNA viruses in the family Flaviviridae.

[6] The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including the intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules.

[citation needed] Most of these viruses are primarily transmitted by the bite from an infected arthropod (mosquito or tick), and hence are classified as arboviruses.

Other virus transmission routes for arboviruses include handling infected animal carcasses, blood transfusion, sex, childbirth and consumption of unpasteurised milk products.

Transmission from nonhuman vertebrates to humans without an intermediate vector arthropod however mostly occurs with low probability.

The known non-arboviruses of the flavivirus family reproduce in either arthropods or vertebrates, but not both, with one odd member of the genus affecting a nematode.

The genome mimics the cellular mRNA molecule in all aspects except for the absence of the poly-adenylated (poly-A) tail.

This feature allows the virus to exploit cellular apparatuses to synthesize both structural and non-structural proteins, during replication.

The N-terminal domain of the non-structural protein 5 (NS5) has both the N7-methyltransferase and guanylyltransferase activities necessary for forming mature RNA cap structures.

RNA binding affinity is reduced by the presence of ATP or GTP and enhanced by S-adenosyl methionine.

Once translated, the polyprotein is cleaved by a combination of viral and host proteases to release mature polypeptide products.

[citation needed] A G protein-coupled receptor kinase 2 (also known as ADRBK1) appears to be important in entry and replication for several viruses in Flaviviridae.

[citation needed] Currently 8 secondary structures have been identified within the 3'UTR of WNV and are (in the order in which they are found with the 3'UTR) SL-I, SL-II, SL-III, SL-IV, DB1, DB2 and CRE.

[20][21] Some of these secondary structures have been characterised and are important in facilitating viral replication and protecting the 3'UTR from 5' endonuclease digestion.

Nuclease resistance protects the downstream 3' UTR RNA fragment from degradation and is essential for virus-induced cytopathicity and pathogenicity.

[citation needed] This secondary structure is located within the 3'UTR of the genome of Flavivirus upstream of the DB elements.

These DB elements have a secondary structure consisting of three helices and they play a role in ensuring efficient translation.

A conserved hairpin (cHP) structure was later found in several Flavivirus genomes and is thought to direct translation of capsid proteins.

[26] sfRNA is produced by incomplete degradation of genomic viral RNA by the host cells 5'-3' exoribonuclease 1 (XRN1).

[31] Overall, sfRNA is implied in multiple pathways that compromise host defenses and promote infection by flaviviruses.

[41] Lineage 1 West Nile virus was detected in South Africa in 2010 in a mare and her aborted fetus; previously, only lineage 2 West Nile virus had been detected in horses and humans in South Africa.

[42] A 2007 fatal case in a killer whale in Texas broadened the known host range of West Nile virus to include cetaceans.

[citation needed] The dengue viruses produce many millions of infections annually due to transmission by a successful global mosquito vector.

CYD-TDV, sold under the trade name Dengvaxia, is a tetravalent chimeric vaccine that splices structural genes of the four dengue viruses onto a 17D yellow fever backbone.

[52] An alternate approach to the development of flavivirus vaccine vectors is based on the use of viruses that infect insects.

Zika virus structure and genome
Replication of Japanese encephalitis virus (JEV)
Replication complex formed on the cytoplasmic side of the ER membrane
Flavivirus RNA genome showing the 3' and 5' UTRs and cyclisation
RNA secondary structure elements of different flavivirus 3′UTRs
Secondary structure of the Flavivirus DB element
Different fates of viral RNA of flaviviruses and formation of sfRNA
Phylogenetic tree of Flavivirus with corresponding vectors and groups
Distribution of major flaviviruses
Phylogenetic tree of Flavivirus with vectors; tick-borne (black), mosquito-borne (purple), with no known vector (red), invertebrate viruses (blue/green)
Distribution of tick-borne encephalitis virus (TBEV), Kyasanur forest disease virus (KFDV), Omsk hemorrhagic fever virus (OHFV), Powassan virus (POWV), and Louping-ill virus (LIV)
Time-line of historical highlights of flavivirus research