Editing Flavivirus

{{Short description|Genus of viruses}}
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{{More citations needed|date=May 2023}}
{{Use dmy dates|date=April 2017}}
{{Virusbox
| image = YellowFeverVirus.jpg
| image_alt = A TEM micrograph of the "Yellow fever virus"
| image_caption = A [[Transmission electron microscope|TEM]] [[micrograph]] of ''[[Yellow fever virus]]''
| image2 = Zika-chain-colored.png
| image2_alt = "Zika virus" capsid model, colored by chains, PDB entry 5ire
| image2_caption = ''Zika virus'' [[viral envelope]] model, colored by chains, [[Protein Data Bank|PDB]] entry {{PDBe|5ire}}<ref name="SirohiChen2016">{{cite journal |vauthors=Sirohi D, Chen Z, Sun L, Klose T, Pierson TC, Rossmann MG, Kuhn RJ |title=The 3.8&nbsp;Å resolution cryo-EM structure of Zika virus |journal=Science |volume=352 |issue=6284 |pages=467–470 |date=April 2016 |pmid=27033547 |pmc=4845755 |doi=10.1126/science.aaf5316 |bibcode=2016Sci...352..467S}}</ref>
| taxon = Flavivirus
| synonyms =
| synonyms_ref =
| subdivision_ranks = Species
| subdivision_ref =
| subdivision =
[[#Taxonomy|See text]]
}}

'''''Flavivirus''''', renamed '''''Orthoflavivirus''''' in 2023,<ref>{{Cite journal |last1=Postler |first1=Thomas S. |last2=Beer |first2=Martin |last3=Blitvich |first3=Bradley J. |last4=Bukh |first4=Jens |last5=de Lamballerie |first5=Xavier |last6=Drexler |first6=J. Felix |last7=Imrie |first7=Allison |last8=Kapoor |first8=Amit |last9=Karganova |first9=Galina G. |last10=Lemey |first10=Philippe |last11=Lohmann |first11=Volker |last12=Simmonds |first12=Peter |last13=Smith |first13=Donald B. |last14=Stapleton |first14=Jack T. |last15=Kuhn |first15=Jens H. |date=2023-08-10 |title=Renaming of the genus Flavivirus to Orthoflavivirus and extension of binomial species names within the family Flaviviridae |journal=Archives of Virology |volume=168 |issue=9 |pages=224 |doi=10.1007/s00705-023-05835-1 |issn=1432-8798 |pmid=37561168|doi-access=free }}</ref> is a genus of [[positive-strand RNA virus]]es in the family ''[[Flaviviridae]]''. The genus includes the [[West Nile virus]], [[dengue virus]], [[tick-borne encephalitis virus]], [[yellow fever virus]], [[Zika virus]] and several other [[virus]]es which may cause [[encephalitis]],<ref name= ShiP-Y>{{cite book | editor= Shi, P-Y | year=2012 | title=Molecular Virology and Control of Flaviviruses | publisher=[[Caister Academic Press]] | isbn= 978-1-904455-92-9}}</ref> as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), [[Palm Creek virus]] (PCV), and [[Parramatta River virus]] (PaRV).<ref name="mclean">{{cite journal|last1=McLean|first1=Breeanna J.|last2=Hobson-Peters|first2=Jody|last3=Webb|first3=Cameron E.|last4=Watterson|first4=Daniel|last5=Prow|first5=Natalie A.|last6=Nguyen|first6=Hong Duyen|last7=Hall-Mendelin|first7=Sonja|last8=Warrilow|first8=David|last9=Johansen|first9=Cheryl A.|last10=Jansen|first10=Cassie C.|last11=van den Hurk|first11=Andrew F.|last12=Beebe|first12=Nigel W.|last13=Schnettler|first13=Esther|last14=Barnard|first14=Ross T.|last15=Hall|first15=Roy A.|title=A novel insect-specific flavivirus replicates only in Aedes-derived cells and persists at high prevalence in wild Aedes vigilax populations in Sydney, Australia|journal=Virology|date=2015|volume=486|pages=272–283|doi=10.1016/j.virol.2015.07.021|pmid=26519596|url=https://www.researchgate.net/publication/283878139|doi-access=free}}</ref> While dual-host flaviviruses can infect [[vertebrate]]s as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods.<ref>{{Cite journal|last1=Elrefaey|first1=Ahmed ME|last2=Abdelnabi|first2=Rana|last3=Rosales Rosas|first3=Ana Lucia|last4=Wang|first4=Lanjiao|last5=Basu|first5=Sanjay|last6=Delang|first6=Leen|date=September 2020|title=Understanding the Mechanisms Underlying Host Restriction of Insect-Specific Viruses|journal=Viruses|language=en|volume=12|issue=9|pages=964|doi=10.3390/v12090964|pmid=32878245|pmc=7552076|doi-access=free}}</ref> 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.<ref>{{Cite journal|last1=Elrefaey|first1=Ahmed M. E.|last2=Hollinghurst|first2=Philippa|last3=Reitmayer|first3=Christine M.|last4=Alphey|first4=Luke|last5=Maringer|first5=Kevin|date=November 2021|title=Innate Immune Antagonism of Mosquito-Borne Flaviviruses in Humans and Mosquitoes|journal=Viruses|language=en|volume=13|issue=11|pages=2116|doi=10.3390/v13112116|pmid=34834923|pmc=8624719|doi-access=free}}</ref>

Flaviviruses are named for the yellow fever virus; the word ''flavus'' means 'yellow' in [[Latin]], and yellow fever in turn is named from its propensity to cause yellow [[jaundice]] in victims.<ref>The earliest mention of "yellow fever" appears in a manuscript of 1744 by [[John Mitchell (geographer)|John Mitchell]] of Virginia; copies of the manuscript were sent to Mr. [[Cadwallader Colden]], a physician in New York, and to [[Benjamin Rush]] of Philadelphia; the manuscript was eventually reprinted in 1814. See:
* Mitchell, John (written: 1744; reprinted: 1814) [https://books.google.com/books?id=_EZJAAAAYAAJ&pg=PA181 "Account of the Yellow fever which prevailed in Virginia in the years 1737, 1741, and 1742, in a letter to the late Cadwallader Colden, Esq. of New York, from the late John Mitchell, M.D.F.R.S. of Virginia"], ''American Medical and Philosophical Register'', '''4''': 181–215.

The term "yellow fever" appears on p. 186.  On p. 188, Mitchell mentions "... the distemper was what is generally called the yellow fever in America."  However, on pages 191–192, he states "... I shall consider the cause of the yellowness which is so remarkable in this distemper, as to have given it the name of the Yellow Fever." Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis.  See: [[Saul Jarcho]] (1957) "John Mitchell, Benjamin Rush, and Yellow fever". ''Bulletin of the History of Medicine'', '''31''' (2): 132–6.</ref>

Flaviviruses share several common aspects: common size (40–65&nbsp;nm), symmetry ([[Envelope (biology)|enveloped]], [[icosahedral]] [[nucleocapsid]]), [[nucleic acid]] ([[positive-sense]], single-stranded [[RNA]] around 10,000–11,000 bases), and appearance under the [[electron microscope]].{{cn|date=February 2024}}

Most of these viruses are primarily transmitted by the bite from an infected [[arthropod]] (mosquito or tick), and hence are classified as [[arboviruses]]. Human infections with most of these arboviruses are incidental, as humans are unable to replicate the virus to high enough [[titer]]s to reinfect the arthropods needed to continue the virus life-cycle&nbsp;– humans are then a [[dead end host]]. The exceptions to this are the ''yellow fever virus'', [[Dengue virus]] and [[Zika virus]]. These three viruses still require mosquito vectors but are well-enough adapted to humans as to not necessarily depend upon animal hosts (although they continue to have important animal transmission routes, as well).

Other virus transmission routes for arboviruses include handling infected animal carcasses, blood transfusion, sex, childbirth and consumption of [[Pasteurization|unpasteurised]] milk products. Transmission from nonhuman vertebrates to humans without an intermediate vector arthropod however mostly occurs with low probability. For example, early tests with yellow fever showed that the disease is not [[Contagious disease|contagious]].

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]].<ref name="ReferenceA">{{cite journal |vauthors=Bekal S, Domier LL, Gonfa B, McCoppin NK, Lambert KN, Bhalerao K |title= A novel flavivirus in the soybean cyst nematode |journal=  Journal of General Virology|doi= 10.1099/vir.0.060889-0 |pmid= 24643877 |volume=95 |issue= Pt 6 |pages=1272–1280|year= 2014 |doi-access= free }}</ref>

==Structure==
[[File:Viruses-10-00597-g001.png|thumb|Zika virus structure and genome]]
Flaviviruses are [[Viral envelope|enveloped]] and spherical and have icosahedral geometries with a pseudo T=3 symmetry. The virus particle diameter is around 50&nbsp;nm.<ref name="ViralZone" />

== Genome ==
Flaviviruses have [[Sense (molecular biology)|positive-sense]], single-stranded RNA [[genome]]s which are non-segmented and around 10–11 kbp in length.<ref name="ViralZone">{{cite web |title=Viral Zone |url=http://viralzone.expasy.org/all_by_species/24.html |publisher=ExPASy |access-date=15 June 2015 |archive-date=17 June 2015 |archive-url=https://web.archive.org/web/20150617192415/http://viralzone.expasy.org/all_by_species/24.html |url-status=dead }}</ref> In general, the genome encodes three structural proteins (Capsid, prM, and Envelope) and seven [[Viral nonstructural protein|non-structural proteins]] (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5).<ref name="researchgate.net">{{cite journal|last1=Rice|first1=C.|last2=Lenches|first2=E.|last3=Eddy|first3=S.|last4=Shin|first4=S.|last5=Sheets|first5=R.|last6=Strauss|first6=J.|title=Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution|journal=Science|date=23 August 1985|volume=229|issue=4715|pages=726–33|doi=10.1126/science.4023707|pmid=4023707|url=https://www.researchgate.net/publication/19137650|access-date=14 November 2016|bibcode=1985Sci...229..726R}}</ref> The genomic RNA is modified at the 5′ end of positive-strand genomic RNA with a cap-1 structure (me<sup>7</sup>-GpppA-me<sup>2</sup>).<ref name="Henderson2011" />

==Life cycle==
[[File:Pathogens-07-00068-g002.webp|thumb|Replication of [[Japanese encephalitis virus]] (JEV)]]
Flaviviruses replicate in the [[cytoplasm]] of the host cells. The genome mimics the cellular [[mRNA]] molecule in all aspects except for the absence of the poly-adenylated [[Poly-A tail|(poly-A) tail]]. This feature allows the virus to exploit cellular apparatuses to synthesize both structural and non-structural proteins, during [[self replication|replication]]. The cellular [[ribosome]] is crucial to the replication of the flavivirus, as it translates the RNA, in a similar fashion to cellular mRNA, resulting in the synthesis of a single [[polyprotein]].<ref name="researchgate.net"/>

Cellular RNA cap structures are formed via the action of an [[RNA triphosphatase]], with [[guanylyltransferase]], N7-[[methyltransferase]] and 2′-O methyltransferase. The virus encodes these activities in its non-structural proteins. The NS3 protein encodes a [[RNA triphosphatase]] within its [[helicase]] domain. It uses the helicase ATP hydrolysis site to remove the γ-phosphate from the 5′ end of the RNA. 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 [[Adenosine triphosphate|ATP]] or [[Guanosine triphosphate|GTP]] and enhanced by [[S-adenosyl methionine]].<ref name=Henderson2011>{{cite journal |vauthors=Henderson BR, Saeedi BJ, Campagnola G, Geiss BJ| year = 2011 | title = Analysis of RNA binding by the Dengue virus NS5 RNA capping enzyme | journal = PLOS ONE | volume = 6 | issue = 10| page = e25795 | doi=10.1371/journal.pone.0025795 | pmid = 22022449 | pmc = 3192115 | editor1-last = Jeang | editor1-first = K.T |bibcode = 2011PLoSO...625795H | doi-access = free }}</ref> This protein also encodes a 2′-O methyltransferase.
[[File:Viruses-07-02837-g002.png|thumb|Replication complex formed on the cytoplasmic side of the [[Endoplasmic reticulum|ER membrane]]]]
Once [[translation (genetics)|translated]], the polyprotein is cleaved by a combination of viral and host [[protease]]s to release mature [[polypeptide]] products.<ref>{{cite journal|last1=Sun|first1=G.|last2=Larsen|first2=C.|last3=Baumgarth|first3=N.|last4=Klem|first4=E|last5=Scheuermann|first5=R.|title=Comprehensive Annotation of Mature Peptides and Genotypes for Zika Virus|journal=PLOS ONE|date=26 January 2017|doi=10.1371/journal.pone.0170462|pmid=28125631|pmc=5268401|volume=12|issue=1|page=e0170462|bibcode=2017PLoSO..1270462S|doi-access=free}}</ref> Nevertheless, cellular post-translational modification is dependent on the presence of a poly-A tail; therefore this process is not host-dependent. Instead, the poly-protein contains an [[autocatalytic]] feature which automatically releases the first peptide, a virus specific enzyme. This enzyme is then able to [[bond cleavage|cleave]] the remaining poly-protein into the individual products. One of the products cleaved is a [[RNA-dependent RNA polymerase]], responsible for the synthesis of a negative-sense RNA molecule. Consequently, this molecule acts as the template for the synthesis of the genomic [[offspring|progeny]] RNA.{{cn|date=October 2022}}

''Flavivirus'' genomic RNA replication occurs on [[rough endoplasmic reticulum]] membranes in membranous compartments. New viral particles are subsequently assembled. This occurs during the [[budding]] process which is also responsible for the accumulation of the envelope and cell [[lysis]].{{cn|date=April 2023}}

A G protein-coupled receptor kinase 2 (also known as ADRBK1) appears to be important in entry and replication for several viruses in ''Flaviviridae''.<ref name="LeSommer2012">{{cite journal |vauthors=Le Sommer C, Barrows NJ, Bradrick SS, Pearson JL, Garcia-Blanco MA| year = 2012 | title = G protein-coupled receptor kinase 2 promotes flaviviridae entry and replication | journal = PLOS Negl Trop Dis | volume = 6 | issue = 9| page = e1820 | doi = 10.1371/journal.pntd.0001820 | pmid = 23029581 | pmc = 3441407 | editor1-last = Michael | editor1-first = Scott F | doi-access = free }}</ref>

Humans, mammals, mosquitoes, and ticks serve as the natural host. Transmission routes are [[zoonosis]] and bite.<ref name="ViralZone" />

{| class="wikitable sortable collapsible collapsed" style="text-align:center"
|-
! 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
|}

==RNA secondary structure elements==
[[File:Fgene-09-00595-g001.jpg|thumb|''Flavivirus'' RNA genome showing the 3' and 5' UTRs and cyclisation]]

The positive sense RNA genome of ''Flavivirus'' contains 5' and 3' [[untranslated region]]s (UTRs).

===5'UTR===
{{main|Flavivirus 5' UTR}}

The 5'UTRs are 95–101 nucleotides long in [[Dengue virus]].<ref name="pmid21994804">{{cite journal|vauthors=Gebhard LG, Filomatori CV, Gamarnik AV | title=Functional RNA elements in the dengue virus genome | journal=Viruses | year= 2011 | volume= 3 | issue= 9 | pages= 1739–56 | pmid=21994804 | doi=10.3390/v3091739 | pmc=3187688 | doi-access=free }}</ref> There are two conserved structural elements in the ''Flavivirus'' 5'UTR, a large stem loop (SLA) and a short stem loop (SLB). SLA folds into a Y-shaped structure with a side stem loop and a small top loop.<ref name="pmid21994804" /><ref name="pmid2829420">{{cite journal|vauthors=Brinton MA, Dispoto JH | title=Sequence and secondary structure analysis of the 5'-terminal region of flavivirus genome RNA | journal=Virology | year= 1988 | volume= 162 | issue= 2 | pages= 290–9 | doi= 10.1016/0042-6822(88)90468-0| pmid=2829420  }}</ref> SLA is likely to act as a promoter, and is essential for viral RNA synthesis.<ref name="pmid16882970">{{cite journal|vauthors=Filomatori CV, Lodeiro MF, Alvarez DE, Samsa MM, Pietrasanta L, Gamarnik AV | title=A 5' RNA element promotes dengue virus RNA synthesis on a circular genome | journal=Genes Dev | year= 2006 | volume= 20 | issue= 16 | pages= 2238–49 | pmid=16882970 | doi=10.1101/gad.1444206 | pmc=1553207 }}</ref><ref name="pmid18234265">{{cite journal|vauthors=Yu L, Nomaguchi M, Padmanabhan R, Markoff L | title=Specific requirements for elements of the 5' and 3' terminal regions in flavivirus RNA synthesis and viral replication | journal=Virology | year= 2008 | volume= 374 | issue= 1 | pages= 170–85 | pmid=18234265 | doi=10.1016/j.virol.2007.12.035 | pmc=3368002 }}</ref> SLB is involved in interactions between the 5'UTR and 3'UTR which result in the cyclisation of the viral RNA, which is essential for viral replication.<ref name="pmid15890901">{{cite journal|vauthors=Alvarez DE, Lodeiro MF, Ludueña SJ, Pietrasanta LI, Gamarnik AV | title=Long-range RNA-RNA interactions circularize the dengue virus genome | journal=J Virol | year= 2005 | volume= 79 | issue= 11 | pages= 6631–43 | pmid=15890901 | doi=10.1128/JVI.79.11.6631-6643.2005 | pmc=1112138 }}</ref>

===3'UTR===
{{main|Flavivirus 3' UTR}}
[[File:Viruses-11-00298-g002.webp|thumb|RNA secondary structure elements of different flavivirus 3′UTRs]]
The 3'UTRs are typically 0.3–0.5&nbsp;kb in length and contain a number of highly conserved [[secondary structure]]s which are conserved and restricted to flaviviruses. The majority of analysis has been carried out using [[West Nile virus]] (WNV) to study the function the 3'UTR.{{cn|date=October 2022}}

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.<ref name="pmid15956576">{{cite journal |vauthors=Chiu WW, Kinney RM, Dreher TW |title=Control of Translation by the 5′- and 3′-Terminal Regions of the Dengue Virus Genome |journal=J. Virol. |volume=79 |issue=13 |pages=8303–15 |date=July 2005 |pmid=15956576 |pmc=1143759 |doi=10.1128/JVI.79.13.8303-8315.2005 }}</ref><ref name="pmid19064258">{{cite journal |vauthors=Pijlman GP, Funk A, Kondratieva N |title=A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity |journal=Cell Host Microbe |volume=4 |issue=6 |pages=579–91 |date=December 2008 |pmid=19064258 |doi=10.1016/j.chom.2008.10.007 |display-authors=etal|doi-access=free }}</ref> 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.{{cn|date=October 2022}}
* '''SL-II'''

SL-II has been suggested to contribute to nuclease resistance.<ref name="pmid19064258"/> It may be related to another [[hairpin loop]] identified in the 5'UTR of the [[Japanese encephalitis virus]] (JEV) genome.<ref name="pmid15113895">{{cite journal |vauthors=Lin KC, Chang HL, Chang RY |title=Accumulation of a 3′-Terminal Genome Fragment in Japanese Encephalitis Virus-Infected Mammalian and Mosquito Cells |journal=J. Virol. |volume=78 |issue=10 |pages=5133–8 |date=May 2004 |pmid=15113895 |pmc=400339 |doi= 10.1128/JVI.78.10.5133-5138.2004}}</ref> The JEV hairpin is significantly over-represented upon host cell infection and it has been suggested that the hairpin structure may play a role in regulating RNA synthesis.{{cn|date=October 2022}}
* '''SL-IV'''

This secondary structure is located within the 3'UTR of the genome of ''Flavivirus'' upstream of the DB elements. The function of this conserved structure is unknown but is thought to contribute to ribonuclease resistance.{{cn|date=October 2022}}
* '''DB1/DB2'''
[[File:RF00525.png|thumb|Secondary structure of the ''Flavivirus'' DB element|upright]]These two conserved secondary structures are also known as pseudo-repeat elements. They were originally identified within the genome of Dengue virus and are found adjacent to each other within the 3'UTR. They appear to be widely conserved across the Flaviviradae. These DB elements have a secondary structure consisting of three helices and they play a role in ensuring efficient translation. Deletion of DB1 has a small but significant reduction in translation but deletion of DB2 has little effect. Deleting both DB1 and DB2 reduced [[translation (biology)|translation]] efficiency of the viral genome to 25%.<ref name="pmid15956576"/>
* '''CRE'''

CRE is the Cis-acting replication element, also known as the 3'SL RNA elements, and is thought to be essential in viral replication by facilitating the formation of a "replication complex".<ref name="pmid9696848">{{cite journal |vauthors=Zeng L, Falgout B, Markoff L |title=Identification of Specific Nucleotide Sequences within the Conserved 3′-SL in the Dengue Type 2 Virus Genome Required for Replication |journal=J. Virol. |volume=72 |issue=9 |pages=7510–22 |date=September 1998 |pmid=9696848 |pmc=109990 |doi= 10.1128/JVI.72.9.7510-7522.1998}}</ref> Although evidence has been presented for an existence of a [[pseudoknot]] structure in this RNA, it does not appear to be well conserved across flaviviruses.<ref name="pmid8672458">{{cite journal |vauthors=Shi PY, Brinton MA, Veal JM, Zhong YY, Wilson WD |title=Evidence for the existence of a pseudoknot structure at the 3' terminus of the flavivirus genomic RNA |journal=Biochemistry |volume=35 |issue=13 |pages=4222–30 |date=April 1996 |pmid=8672458 |doi=10.1021/bi952398v }}</ref> Deletions of the 3' UTR of flaviviruses have been shown to be lethal for infectious clones.

===Conserved hairpin cHP===
A [[Flavivirus capsid hairpin cHP|conserved hairpin (cHP)]] structure was later found in several ''Flavivirus'' [[genome]]s and is thought to direct translation of capsid proteins. It is located just downstream of the AUG [[start codon]].<ref>{{cite journal |author1= Clyde K, Harris E |title= RNA Secondary Structure in the Coding Region of Dengue Virus Type 2 Directs Translation Start Codon Selection and Is Required for Viral Replication |journal= J Virol |volume= 80 |issue=  5|pages= 2170–2182 |year= 2006 |pmid=16474125 |doi= 10.1128/JVI.80.5.2170-2182.2006 |pmc= 1395379}}</ref>

== The role of RNA secondary structures in sfRNA production ==
[[File:Fgene-09-00595-g002.jpg|thumb|Different fates of viral RNA of flaviviruses and formation of sfRNA]]

Subgenomic flavivirus RNA (sfRNA) is an extension of the 3' UTR and has been demonstrated to play a role in flavivirus replication and pathogenesis.<ref>{{Cite journal|last1=Bidet|first1=Katell|last2=Garcia-Blanco|first2=Mariano A.|date=2014-09-01|title=Flaviviral RNAs: weapons and targets in the war between virus and host|journal=Biochemical Journal|language=en|volume=462|issue=2|pages=215–230|doi=10.1042/BJ20140456|issn=0264-6021|pmid=25102029}}</ref> sfRNA is produced by incomplete degradation of genomic viral RNA by the host cells [[5'-3' exoribonuclease 1]] (XRN1).<ref>{{Cite journal|last1=Chapman|first1=Erich G.|last2=Costantino|first2=David A.|last3=Rabe|first3=Jennifer L.|last4=Moon|first4=Stephanie L.|last5=Wilusz|first5=Jeffrey|last6=Nix|first6=Jay C.|last7=Kieft|first7=Jeffrey S.|date=2014-04-18|title=The Structural Basis of Pathogenic Subgenomic Flavivirus RNA (sfRNA) Production|journal=Science|language=en|volume=344|issue=6181|pages=307–310|doi=10.1126/science.1250897|issn=0036-8075|pmc=4163914|pmid=24744377|bibcode=2014Sci...344..307C}}</ref> As the XRN1 degrades viral RNA, it stalls at stemloops formed by the secondary structure of the 5' and 3' UTR.<ref>{{Cite journal|last1=Funk|first1=Anneke|last2=Truong|first2=Katherine|last3=Nagasaki|first3=Tomoko|last4=Torres|first4=Shessy|last5=Floden|first5=Nadia|last6=Melian|first6=Ezequiel Balmori|last7=Edmonds|first7=Judy|last8=Dong|first8=Hongping|last9=Shi|first9=Pei-Yong|date=2010-11-01|title=RNA Structures Required for Production of Subgenomic Flavivirus RNA|journal=Journal of Virology|language=en|volume=84|issue=21|pages=11407–11417|doi=10.1128/JVI.01159-10|issn=0022-538X|pmc=2953152|pmid=20719943}}</ref> This pause results in an undigested fragment of genome RNA known as sfRNA. sfRNA influences the life cycle of the flavivirus in a concentration dependent manner. Accumulation of sfRNA causes (1) antagonization of the cell's innate immune response, thus decreasing host defense against the virus<ref>{{Cite journal|last1=Chang|first1=Ruey-Yi|last2=Hsu|first2=Ta-Wen|last3=Chen|first3=Yen-Lin|last4=Liu|first4=Shu-Fan|last5=Tsai|first5=Yi-Jer|last6=Lin|first6=Yun-Tong|last7=Chen|first7=Yi-Shiuan|last8=Fan|first8=Yi-Hsin|date=2013-09-27|title=Japanese encephalitis virus non-coding RNA inhibits activation of interferon by blocking nuclear translocation of interferon regulatory factor 3|journal=Veterinary Microbiology|volume=166|issue=1–2|pages=11–21|doi=10.1016/j.vetmic.2013.04.026|pmid=23755934}}</ref> (2) inhibition of XRN1 and Dicer activity to modify RNAi pathways that destroy viral RNA<ref>{{Cite journal|last1=Moon|first1=Stephanie L.|last2=Anderson|first2=John R.|last3=Kumagai|first3=Yutaro|last4=Wilusz|first4=Carol J.|last5=Akira|first5=Shizuo|last6=Khromykh|first6=Alexander A.|last7=Wilusz|first7=Jeffrey|date=2012-11-01|title=A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability|journal=RNA|language=en|volume=18|issue=11|pages=2029–2040|doi=10.1261/rna.034330.112|issn=1355-8382|pmc=3479393|pmid=23006624}}</ref> (3) modification of the viral replication complex to increase viral reproduction.<ref>{{Cite journal|last1=Clarke|first1=B. D.|last2=Roby|first2=J. A.|last3=Slonchak|first3=A.|last4=Khromykh|first4=A. A.|date=2015-08-03|title=Functional non-coding RNAs derived from the flavivirus 3′ untranslated region|journal=Virus Research|series=Special Issue: Functions of the ends of positive strand RNA virus genomes|volume=206|pages=53–61|doi=10.1016/j.virusres.2015.01.026|pmid=25660582}}</ref> Overall, sfRNA is implied in multiple pathways that compromise host defenses and promote infection by flaviviruses.{{cn|date=October 2022}}

== Evolution ==
[[File:Fimmu-11-00334-g001.jpg|thumb|[[Phylogenetic tree]] of ''Flavivirus'' with corresponding vectors and groups]]
The flaviviruses can be divided into two clades: one with vector-borne viruses and the other with no known vector.<ref name=Kuno1998>{{cite journal |vauthors=Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, Cropp CB | year = 1998 | title = Phylogeny of the genus Flavivirus | journal = J Virol | volume = 72 | issue = 1| pages = 73–83 | pmid = 9420202 | pmc = 109351 | doi = 10.1128/JVI.72.1.73-83.1998 }}</ref> The vector clade, in turn, can be subdivided into a mosquito-borne clade and a tick-borne clade. These groups can be divided again.<ref name=Gaunt2001>{{cite journal |vauthors=Gaunt MW, Sall AA, de Lamballerie X, Falconar AK, Dzhivanian TI, Gould EA | year = 2001 | title = Phylogenetic relationships of flaviviruses correlate with their epidemiology, disease association and biogeography | doi = 10.1099/0022-1317-82-8-1867 | pmid = 11457992 | journal = J Gen Virol | volume = 82 | issue = 8| pages = 1867–1876 | doi-access = free }}</ref>

The mosquito group can be divided into two branches: one branch contains neurotropic viruses, often associated with encephalitic disease in humans or livestock. This branch tends to be spread by ''[[Culex]]'' species and to have bird reservoirs. The second branch is the non-neurotropic viruses associated with human haemorrhagic disease. These tend to have ''[[Aedes]]'' species as vectors and [[primate]] hosts.{{cn|date=October 2022}}

The tick-borne viruses also form two distinct groups: one is associated with [[seabird]]s and the other – the tick-borne encephalitis complex viruses – is associated primarily with [[rodent]]s.{{cn|date=October 2022}}

The viruses that lack a known vector can be divided into three groups: one closely related to the mosquito-borne viruses, which is associated with [[bat]]s; a second, genetically more distant, is also associated with bats; and a third group is associated with rodents.{{cn|date=October 2022}}

Evolutionary relationships between endogenised viral elements of Flaviviruses and contemporary flaviviruses using maximum likelihood approaches have identified that arthropod-vectored flaviviruses likely emerged from an arachnid source.<ref name="pmid36533146">{{cite journal| author=Bamford CGG, de Souza WM, Parry R, Gifford RJ| title=Comparative analysis of genome-encoded viral sequences reveals the evolutionary history of flavivirids (family Flaviviridae). | journal=Virus Evol | year= 2022 | volume= 8 | issue= 2 | pages= veac085 | pmid=36533146 | doi=10.1093/ve/veac085 | pmc=9752770 }} </ref> This contradicts earlier work with a smaller number of extant viruses showing that the tick-borne viruses emerged from a mosquito-borne group.<ref name=Cook2006>{{cite journal |vauthors=Cook S, Holmes EC | year = 2006 | title = A multigene analysis of the phylogenetic relationships among the flaviviruses (Family: Flaviviridae) and the evolution of vector transmission | journal = Arch Virol | volume = 151 | issue = 2| pages = 309–325 | doi = 10.1007/s00705-005-0626-6 | pmid = 16172840 | doi-access = free }}</ref>

Several partial and complete genomes of flaviviruses have been found in aquatic invertebrates such as the [[sea spider]] ''Endeis spinosa''<ref name=Conway2015>{{cite journal | author = Conway MJ | year = 2015 | title = Identification of a flavivirus sequence in a marine arthropod | journal = PLOS ONE | volume = 10 | issue = 12| page = e0146037 | doi = 10.1371/journal.pone.0146037 | pmid=26717191 | pmc=4699914| bibcode = 2015PLoSO..1046037C | doi-access = free }}</ref> and several crustaceans and cephalopods.<ref name="pmid31068424">{{cite journal| author=Parry R, Asgari S| title=Discovery of Novel Crustacean and Cephalopod Flaviviruses: Insights into the Evolution and Circulation of Flaviviruses between Marine Invertebrate and Vertebrate Hosts. | journal=J Virol | year= 2019 | volume= 93 | issue= 14 | pages=  | pmid=31068424 | doi=10.1128/JVI.00432-19 | pmc=6600200 }} </ref> These sequences appear to be related to those in the insect-specific flaviviruses and also the Tamana bat virus groupings. While it is not presently clear how aquatic flaviviruses fit into the evolution of this group of viruses, there is some evidence that one of these viruses, Wenzhou shark flavivirus, infects both a crustacean (''Portunus trituberculatus'') Pacific spadenose shark (''Scoliodon macrorhynchos'') shark host,<ref name="pmid29618816">{{cite journal| author=Shi M, Lin XD, Chen X, Tian JH, Chen LJ, Li K | display-authors=etal| title=The evolutionary history of vertebrate RNA viruses. | journal=Nature | year= 2018 | volume= 556 | issue= 7700 | pages= 197–202 | pmid=29618816 | doi=10.1038/s41586-018-0012-7 | pmc= | bibcode=2018Natur.556..197S| s2cid=256771319| url=https://pubmed.ncbi.nlm.nih.gov/29618816  }} </ref><ref name="pmid31068424"/> indicating an aquatic arbovirus life cycle.
[[File:Viruses-09-00097-g001.png|thumb|Distribution of major flaviviruses]]
Estimates of divergence times have been made for several of these viruses.<ref name="Moureau2015">{{Cite journal |doi = 10.1371/journal.pone.0117849|pmid = 25719412|pmc = 4342338|title = New Insights into Flavivirus Evolution, Taxonomy and Biogeographic History, Extended by Analysis of Canonical and Alternative Coding Sequences|journal = PLOS ONE|volume = 10|issue = 2|pages = e0117849|year = 2015|last1 = Moureau|first1 = Gregory|last2 = Cook|first2 = Shelley|last3 = Lemey|first3 = Philippe|last4 = Nougairede|first4 = Antoine|last5 = Forrester|first5 = Naomi L.|last6 = Khasnatinov|first6 = Maxim|last7 = Charrel|first7 = Remi N.|last8 = Firth|first8 = Andrew E.|last9 = Gould|first9 = Ernest A.|last10 = De Lamballerie|first10 = Xavier|bibcode = 2015PLoSO..1017849M|doi-access = free}}</ref> The origin of these viruses appears to be at least 9400 to 14,000 years ago. The Old World and New World dengue strains diverged between 150 and 450 years ago. The European and Far Eastern tick-borne encephalitis strains diverged about 1087 (1610–649) years ago. European tick-borne encephalitis and louping ill viruses diverged about 572 (844–328) years ago. This latter estimate is consistent with historical records. Kunjin virus diverged from West Nile virus approximately 277 (475–137) years ago. This time corresponds to the settlement of Australia from Europe. The Japanese encephalitis group appears to have evolved in Africa 2000–3000 years ago and then spread initially to South East Asia before migrating to the rest of Asia.

[[Phylogeny|Phylogenetic]] studies of the West Nile virus has shown that it emerged as a distinct virus around 1000 years ago.<ref>{{cite journal |vauthors=Galli M, Bernini F, Zehender G |title=Alexander the Great and West Nile virus encephalitis |journal=Emerging Infect. Dis. |volume=10 |issue=7 |pages=1330–2; author reply 1332–3 |date=July 2004 |pmid=15338540 |doi=10.3201/eid1007.040396 |doi-access=free }}</ref> This initial virus developed into two distinct lineages, lineage 1 and its multiple profiles is the source of the epidemic transmission in Africa and throughout the world. Lineage 2 was considered an Africa [[zoonosis]]. However, in 2008, lineage 2, previously only seen in horses in sub-Saharan Africa and Madagascar, began to appear in horses in Europe, where the first known outbreak affected 18 animals in Hungary in 2008.<ref>{{cite journal| url=http://www.thehorse.com/ViewArticle.aspx?ID=15779|title=Different West Nile Virus Genetic Lineage Evolving?|author=West, Christy|journal=The Horse |date = 2010-02-08 |access-date=2010-02-10}} From statements by Orsolya Kutasi, DVM, of the Szent Istvan University, Hungary at the 2009 American Association of Equine Practitioners Convention, December 5–9, 2009.</ref> 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.<ref>{{cite journal |vauthors=Venter M, Human S, van Niekerk S, Williams J, van Eeden C, Freeman F |title=Fatal neurologic disease and abortion in mare infected with lineage 1 West Nile virus, South Africa |journal=Emerging Infect. Dis. |volume=17 |issue=8 |pages=1534–6 |date=August 2011 |pmid=21801644 |pmc=3381566 |doi=10.3201/eid1708.101794 }}</ref> A 2007 fatal case in a [[killer whale]] in [[Texas]] broadened the known [[host range]] of West Nile virus to include [[cetacean]]s.<ref>{{cite journal |vauthors=St Leger J, Wu G, Anderson M, Dalton L, Nilson E, Wang D |title=West Nile virus infection in a killer whale, Texas, USA, 2007 |journal=Emerging Infect. Dis. |volume=17 |issue=8 |pages=1531–3 |year=2011 |pmid=21801643 |pmc=3381582 |doi=10.3201/eid1708.101979 }}</ref>

Omsk haemorrhagic fever virus appears to have evolved within the last 1000 years.<ref name="Karan2013">{{Cite journal |doi=10.1002/jmv.23856|pmid=24259273|title=The deduced evolution history of Omsk hemorrhagic fever virus|journal=Journal of Medical Virology|volume=86|issue=7|pages=1181–1187|year=2014|last1=Karan|first1=Liudmila S.|last2=Ciccozzi|first2=Massimo|last3=Yakimenko|first3=Valerii V.|last4=Presti|first4=Alessandra Lo|last5=Cella|first5=Eleonora|last6=Zehender|first6=Gianguglielmo|last7=Rezza|first7=Giovanni|last8=Platonov|first8=Alexander E.|s2cid=36929638}}</ref> The viral genomes can be divided into 2 clades — A and B. Clade A has five genotypes, and clade B has one. These clades separated about 700 years ago. This separation appears to have occurred in the Kurgan province. Clade A subsequently underwent division into clade C, D and E 230 years ago. Clade C and E appear to have originated in the Novosibirsk and Omsk Provinces, respectively. The muskrat ''[[Ondatra zibethicus]]'', which is highly susceptible to this virus, was introduced into this area in the 1930s.

==Taxonomy==

=== Species ===
The genus contains the following species, listed by scientific name and followed by their common names:<ref>{{cite web|title=Virus Taxonomy: 2024 Release|url=https://ictv.global/taxonomy|publisher=International Committee on Taxonomy of Viruses|access-date=12 March 2025}}</ref>

{{div col}}
* ''Orthoflavivirus apoiense'', [[Apoi virus]]
* ''Orthoflavivirus aroaense'', [[Aroa virus]]
* ''Orthoflavivirus bagazaense'', [[Bagaza virus]]
* ''Orthoflavivirus banziense'', [[Banzi virus]]
* ''Orthoflavivirus boubouiense'', [[Bouboui virus]]
* ''Orthoflavivirus bravoense'', [[Rio Bravo virus]]
* ''Orthoflavivirus bukalasaense'', [[Bukalasa bat virus]]
* ''Orthoflavivirus cacipacoreense'', [[Cacipacore virus]]
* ''Orthoflavivirus careyense'', [[Carey Island virus]]
* ''Orthoflavivirus cowboneense'', [[Cowbone Ridge virus]]
* ''Orthoflavivirus dakarense'', [[Dakar bat virus]]
* ''Orthoflavivirus denguei'', [[Dengue virus]]
* ''Orthoflavivirus edgehillense'', [[Edge Hill virus]]
* ''Orthoflavivirus encephalitidis'', [[Tick-borne encephalitis virus]]
* ''Orthoflavivirus entebbeense'', [[Entebbe bat virus]]
* ''Orthoflavivirus flavi'', [[Yellow fever virus]]
* ''Orthoflavivirus gadgetsense'', [[Gadgets Gully virus]]
* ''Orthoflavivirus ilheusense'', [[Ilhéus virus|Ilheus virus]]
* ''Orthoflavivirus israelense'', [[Israel turkey meningoencephalomyelitis virus]]
* ''Orthoflavivirus japonicum'', [[Japanese encephalitis virus]]
* ''Orthoflavivirus jugraense'', [[Jugra virus]]
* ''Orthoflavivirus jutiapaense'', [[Jutiapa virus]]
* ''Orthoflavivirus kadamense'', [[Kadam virus]]
* ''Orthoflavivirus kedougouense'', [[Kedougou virus]]
* ''Orthoflavivirus kokoberaorum'', [[Kokobera virus]]
* ''Orthoflavivirus koutangoense'', [[Koutango virus]]
* ''Orthoflavivirus kyasanurense'', [[Kyasanur Forest disease virus]]
* ''Orthoflavivirus langatense'', [[Langat virus]]
* ''Orthoflavivirus louisense'', [[Saint Louis encephalitis virus]]
* ''Orthoflavivirus loupingi'', [[Louping ill virus]]
* ''Orthoflavivirus meabanense'', [[Meaban virus]]
* ''Orthoflavivirus modocense'', [[Modoc virus]]
* ''Orthoflavivirus montanaense'', [[Montana myotis leukoencephalitis virus]]
* ''Orthoflavivirus murrayense'', [[Murray Valley encephalitis virus]]
* ''Orthoflavivirus nilense'', [[West Nile virus]]
* ''Orthoflavivirus ntayaense'', [[Ntaya virus]]
* ''Orthoflavivirus omskense'', [[Omsk hemorrhagic fever virus]]
* ''Orthoflavivirus perlitaense'', [[San Perlita virus]]
* ''Orthoflavivirus phnompenhense'', [[Phnom Penh bat virus]]
* ''Orthoflavivirus powassanense'', [[Powassan virus]]
* ''Orthoflavivirus royalense'', [[Royal Farm virus]]
* ''Orthoflavivirus saboyaense'', [[Saboya virus]]
* ''Orthoflavivirus saumarezense'', [[Saumarez Reef virus]]
* ''Orthoflavivirus sepikense'', [[Sepik virus]]
* ''Orthoflavivirus tembusu'', [[Tembusu virus]]
* ''Orthoflavivirus tyuleniyense'', [[Tyuleniy virus]]
* ''Orthoflavivirus ugandaense'', [[Uganda S virus]]
* ''Orthoflavivirus usutuense'', [[Usutu virus]]
* ''Orthoflavivirus viejaense'', [[Sal Vieja virus]]
* ''Orthoflavivirus wesselsbronense'', [[Wesselsbron virus]]
* ''Orthoflavivirus yaoundeense'', [[Yaounde virus]]
* ''Orthoflavivirus yokoseense'', [[Yokose virus]]
* ''Orthoflavivirus zikaense'', [[Zika virus]]
{{div col end}}

===Sorted by vector===
<!-- Note that this list includes recognized and unrecognized species. -->
{{hidden|List of species and strains of flavivirus by vector|

{{Columns-list|colwidth=15em|

[[File:Viruses-09-00154-g001.webp|thumb|Phylogenetic tree of ''Flavivirus'' with vectors; tick-borne (black), mosquito-borne (purple), with no known vector (red), invertebrate viruses (blue/green)|left]]
Species and strains sorted by vectors:

===Tick-borne viruses===

[[File:Viruses-10-00340-g001.png|thumb|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)|left]]
[[Mammal]]ian tick-borne virus group
* [[Greek goat encephalitis virus]] (GGEV)
* [[Kadam virus]] (KADV)
* [[Krasnodar virus]] (KRDV)
* [[Mogiana tick virus]] (MGTV)
* [[Ngoye virus]] (NGOV)
* [[Sokuluk virus]] (SOKV)
* [[Spanish sheep encephalomyelitis virus]] (SSEV)
* [[Turkish sheep encephalitis virus]] (TSE)
* Tick-borne encephalitis virus serocomplex
** [[Absettarov virus]]
** [[Deer tick virus]] (DT)
** [[Gadgets Gully virus]] (GGYV)
** [[Karshi virus]]
** [[Kyasanur Forest disease virus]] (KFDV)
*** [[Alkhurma hemorrhagic fever virus]] (ALKV)
** [[Langat virus]] (LGTV)
** [[Louping ill virus]] (LIV)
** [[Omsk hemorrhagic fever virus]] (OHFV)
** [[Powassan virus]] (POWV)
** [[Royal Farm virus]] (RFV)
** [[Tick-borne encephalitis virus]] (TBEV)

[[Seabird]] tick-borne virus group
* [[Kama virus]] (KAMV)
* [[Meaban virus]] (MEAV)
* [[Saumarez Reef virus]] (SREV)
* [[Tyuleniy virus]] (TYUV)

=== Mosquito-borne viruses ===
* Without known vertebrate host
** Cell fusing clade
*** [[Aedes flavivirus]]
*** [[Cell fusing agent virus]]
** [[Aedes galloisi flavivirus]]
** [[Barkedji virus]]
** [[Calbertado virus]]
** [[Chaoyang virus]]
** [[Culex flavivirus]]
** [[Culex theileri flavivirus]]
*** [[Spanish Culex flavivirus]]
*** [[Wang Thong virus]]
** [[Culiseta flavivirus]]
** [[Donggang virus]]
** [[Hanko virus]]
*** [[Ochlerotatus caspius flavivirus]]
*** [[Spanish Ochlerotatus flavivirus]]
** [[Ilomantsi virus]]
** [[Kamiti River virus]]
** [[Lammi virus]]
** [[Marisma mosquito virus]]
** [[Nakiwogo virus]]
** [[Nhumirim virus]]
** [[Nienokoue virus]]
** [[Nounané virus]]
** [[Palm Creek virus]]
** [[Panmunjeom flavivirus]]
** [[Quang Binh virus]]
*** [[Yunnan Culex flavivirus]]
* Aroa virus group
** [[Aroa virus]] (AROAV)
** [[Bussuquara virus]] (BSQV)
** [[Iguape virus]] (IGUV)
** [[Naranjal virus]] (NJLV)
* Dengue virus group
** [[Dengue virus]] (DENV)
** [[Kedougou virus]] (KEDV)<ref name="pmid677616">{{cite journal| author=Robin Y, Cornet M, Le Gonidec G, Chateau R, Heme G| title=[Kedougou virus (Ar D14701): a new Arbovirus ("Flavivirus") isolated in Senegal (author's transl)]. | journal=Ann Microbiol (Paris) | year= 1978 | volume= 129 | issue= 2 | pages= 239–44 | pmid=677616 | doi= | pmc= | url=https://pubmed.ncbi.nlm.nih.gov/677616  }}</ref><ref name="pmid34372574">{{cite journal| author=Jansen van Vuren P, Parry R, Khromykh AA, Paweska JT| title=A 1958 Isolate of Kedougou Virus (KEDV) from Ndumu, South Africa, Expands the Geographic and Temporal Range of KEDV in Africa. | journal=Viruses | year= 2021 | volume= 13 | issue= 7 | page=1368 | pmid=34372574 | doi=10.3390/v13071368 | pmc=8309962 | doi-access=free }}</ref>
* Japanese encephalitis virus group
** [[Cacipacore virus]] (CPCV)
** [[Koutango virus]] (KOUV)
** [[Kunjin virus]]
** [[Ilheus virus]] (ILHV)
** [[Japanese encephalitis virus]] (JEV)
** [[Murray Valley encephalitis virus]] (MVEV)
*** [[Alfuy virus]]
** [[St. Louis Encephalitis|St. Louis encephalitis virus]] (SLEV)
** [[Usutu virus]] (USUV)
** [[West Nile virus]] (WNV)
** [[Yaounde virus]] (YAOV)
* Kokobera virus group
** [[Kokobera virus]] (KOKV)
** [[New Mapoon virus]] (NMV)
** [[Stratford virus]] (STRV)
* Ntaya virus group
** [[Bagaza virus]] (BAGV)
** [[Baiyangdian virus]] (BYDV)
** [[Duck egg drop syndrome virus]] (DEDSV)
** [[Ilheus virus]] (ILHV)
** [[Israel turkey meningoencephalomyelitis virus]] (ITV)
** [[Jiangsu virus]] (JSV)
** [[Layer flavivirus]]
** [[Ntaya virus]] (NTAV)
** [[Rocio virus]] (ROCV)
** [[Sitiawan virus]] (STWV)
** [[T'Ho virus]]
** [[Tembusu virus]] (TMUV)
* Spondweni virus group
** [[Spondweni virus]] (SPOV)
** [[Zika virus]] (ZIKV)
* Yellow fever virus group
** [[Banzi virus]] (BANV)
** [[Bamaga virus]] (BGV)
** [[Bouboui virus]] (BOUV)
** [[Edge Hill virus]] (EHV)
** [[Fitzroy river virus]]
** [[Jugra virus]] (JUGV)
** [[Saboya virus]] (SABV)
** [[Sepik virus]] (SEPV)
** [[Uganda S virus]] (UGSV)
** [[Wesselsbron virus]] (WESSV)
** [[Yellow fever virus]] (YFV)
* Others
** [[Batu cave virus]]
** [[Bukulasa bat virus]]
** [[Nanay virus]]
** [[Rabensburg virus]] (RABV)
** [[Sitiawan virus]]

===Viruses with no known arthropod vector===
* [[Tamana bat virus]] (TABV)
* Entebbe virus group
** [[Entebbe bat virus]] (ENTV)
*** [[Sokoluk virus]]
** [[Yokose virus]] (YOKV)
* Modoc virus group
** [[Apoi virus]] (APOIV)
** [[Cowbone Ridge virus]] (CRV)
** [[Jutiapa virus]] (JUTV)
** [[Modoc virus]] (MODV)
** [[Sal Vieja virus]] (SVV)
** [[San Perlita virus]] (SPV)
* Rio Bravo virus group
** [[Bukalasa bat virus]] (BBV)
** [[Carey Island virus]] (CIV)
** [[Dakar bat virus]] (DBV)
** [[Montana myotis leukoencephalitis virus]] (MMLV)
** [[Phnom Penh bat virus]] (PPBV)
** [[Rio Bravo virus]] (RBV)

===Non vertebrate viruses===
* [[Assam virus]]
* [[Bamaga virus]]<ref>{{cite journal|last1=van den Hurk|first1=Andrew F.|last2=Suen|first2=Willy W.|last3=Hall|first3=Roy A.|last4=O'Brien|first4=Caitlin A.|last5=Bielefeldt-Ohmann|first5=Helle|last6=Hobson-Peters|first6=Jody|last7=Colmant|first7=Agathe M. G.|s2cid=43127614|title=A newly discovered flavivirus in the yellow fever virus group displays restricted replication in vertebrates|journal=Journal of General Virology|date=2016|volume=97|issue=5|pages=1087–1093|doi=10.1099/jgv.0.000430|pmid=26878841|doi-access=free}}</ref>
* [[Crangon crangon flavivirus]]<ref name="Parry2019">{{cite journal |last1=Parry |first1=Rhys|last2=Asgari|first2=Sassan |title=Discovery of Novel Crustacean and Cephalopod Flaviviruses: Insights into the Evolution and Circulation of Flaviviruses between Marine Invertebrate and Vertebrate Hosts |journal=Journal of Virology |date=15 July 2019 |volume=93 |issue=14 |doi=10.1128/JVI.00432-19 |pmid=31068424|pmc=6600200}}</ref>
* [[Cuacua virus]]
* [[Donggang virus]]
* [[Firefly squid flavivirus]]<ref name="Parry2019"/>
* [[Gammarus chevreuxi flavivirus]]<ref name="Parry2019"/>
* [[Gammarus pulex flavivirus]]<ref name="Parry2019"/>
* [[Karumba virus]] (KRBV)
* [[Hanko virus]]
* [[Haslams Creek virus]]
* [[Mac Peak virus]] (McPV)
* [[Marisma mosquito virus]]
* [[Mediterranean Ochlerotatus flavivirus]]
* [[Menghai flavivirus]]
* [[Nakiwogo virus]] (NAKV)
* [[Nanay virus]]
* [[Nounané virus]]
* [[Ochlerotatus caspius flavivirus]]
* [[Palm Creek virus]]
* [[Parramatta River virus]]
* [[Southern Pygmy squid flavivirus]]<ref name="Parry2019"/>
* [[Soybean cyst nematode virus 5]]<ref name="ReferenceA"/>
* [[Xishuangbanna Aedes flavivirus]]

===Viruses known only from sequencing===
* [[Aedes flavivirus]]
* [[Aedes cinereus flavivirus]]
* [[Aedes vexans flavivirus]]
* [[Culex theileri flavivirus]]

}}
}}

==Vaccines==
[[File:Viruses-09-00097-g002.png|thumb|Time-line of historical highlights of flavivirus research]]
The very successful [[Yellow fever vaccine|yellow fever 17D vaccine]], introduced in 1937, produced dramatic reductions in epidemic activity.{{cn|date=October 2022}}

Effective inactivated [[Japanese encephalitis]] and [[Tick-borne encephalitis]] vaccines were introduced in the middle of the 20th century. Unacceptable adverse events have prompted change from a mouse-brain inactivated [[Japanese encephalitis vaccine]] to safer and more effective second generation Japanese encephalitis vaccines. These may come into wide use to effectively prevent this severe disease in the huge populations of Asia—North, South and Southeast.{{cn|date=October 2022}}

The dengue viruses produce many millions of infections annually due to transmission by a successful global mosquito vector. As mosquito control has failed, several [[dengue vaccine]]s are in varying stages of development. 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.<ref name=Thisyakorn2014>{{cite journal | doi = 10.1177/2051013613507862 | pmid=24757522 | pmc=3991153 | title=Latest developments and future directions in dengue vaccines | journal=Therapeutic Advances in Vaccines | date=2014 | volume=2 | issue=1 | pages=3–9 | first=U. | last=Thisyakorn}}</ref><ref name=Yauch2014>{{cite book | doi = 10.1016/B978-0-12-800098-4.00007-6 | pmid=24373316 | title=Dengue Virus Vaccine Development | volume=88 | date=2014 | pages=315–372 | first=Lauren E. | last=Yauch| series=Advances in Virus Research | isbn=978-0-12-800098-4 }}</ref> Dengvaxia is approved in five countries.<ref>{{Cite web |url=https://www.who.int/immunization/research/development/dengue_q_and_a/en/ |title=WHO Questions and Answers on Dengue Vaccines |publisher=WHO.int |access-date=2016-10-01}}</ref>

{{blockquote|An alternate approach to the development of flavivirus vaccine vectors is based on the use of viruses that infect insects. Insect-specific flaviviruses, such as Binjari virus, are unable to replicate in vertebrate cells. Nevertheless, recombinant viruses in which structural protein genes (prME) of Binjari virus are exchanged with those of dengue virus, Zika virus, West Nile virus, yellow fever virus, or Japanese encephalitis virus replicate efficiently in insect cells where high titers of infectious virus particles are produced. [[Zika virus vaccine#Viral vector-based vaccines|Immunization of mice with a Binjari vaccine bearing the Zika virus structural proteins protected mice from disease after challenge]]. A similar approach employs the insect-specific [[alphavirus]] [[Eilat virus]] as a [[vaccine platform]]. ... These new vaccine platforms generated from insect-specific flaviviruses and alphaviruses represent affordable, efficient, and safe approaches to rapid development of infectious, attenuated vaccines against pathogens from these two virus families.<ref>{{cite book|author=Flint J|author2=Racaniello VR|author3=Rall GF|author4=Hatziiannou T|author5=Skalka AM|url=https://books.google.com/books?id=Kjz1DwAAQBAJ&pg=PA327| page=327 | edition=5th |isbn=978-1-68367-283-8 | title=Principles of Virology, Volume 2: Pathogenesis and Control | date=3 August 2020 | publisher=John Wiley & Sons }}</ref>}}

==References==
{{Reflist|30em}}

==Further reading==
* {{cite journal |vauthors=Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, Cropp CB |date=Jan 1998 | title = Phylogeny of the genus ''Flavivirus'' | pmid=9420202 | journal = J Virol | volume = 72 | issue = 1| pages = 73–83 | pmc=109351|doi=10.1128/JVI.72.1.73-83.1998 }}
* {{cite journal|last1=Zanotto|first1=P. M.|last2=Gould|first2=E. A.|last3=Gao|first3=G. F.|last4=Harvey|first4=P. H.|last5=Holmes|first5=E. C.|title=Population dynamics of flaviviruses revealed by molecular phylogenies.|journal=Proceedings of the National Academy of Sciences|date=1996|volume=93|issue=2|pages=548–553|doi=10.1073/pnas.93.2.548| pmc=40088 |pmid=8570593| bibcode = 1996PNAS...93..548Z|doi-access=free}}
* {{cite book|last1=Kalitzky|first1=Matthias|title=Molecular Biology of the Flavivirus|year=2006|publisher=Horizon Bioscience|location=Wymondham|isbn=978-1-904933-22-9}}
* {{cite book|last1=Shi|first1=Pei-Yong|title=Molecular Virology and Control of Flaviviruses|year=2012|publisher=Caister Academic Press|location=Norfolk, UK|isbn=978-1-904455-92-9}}
* {{cite journal|last1=Murray|first1=Catherine L.|last2=Jones|first2=Christopher T.|last3=Rice|first3=Charles M.|title=Architects of assembly: roles of Flaviviridae non-structural proteins in virion morphogenesis|journal=Nature Reviews Microbiology|date=2008|volume=6|issue=9|pages=699–708|doi=10.1038/nrmicro1928|pmid=18587411|pmc=2764292}}

==External links==
* [https://web.archive.org/web/20150423185007/http://www.microbiologybytes.com/virology/Flaviviruses.html MicrobiologyBytes: Flaviviruses]
* [https://web.archive.org/web/20061114012418/http://www.nitd.novartis.com/focus_areas/dengue.shtml Novartis Institute for Tropical Diseases (NITD)] – Dengue Fever research at the Novartis Institute for Tropical Diseases (NITD)
* [https://web.archive.org/web/20061208145541/http://www.dengueinfo.org/ Dengueinfo.org] – Depository of dengue virus genomic sequence data
* [http://www.expasy.org/viralzone/all_by_species/24.html '''Viralzone''': Flavivirus] {{Webarchive|url=https://web.archive.org/web/20100613174515/http://expasy.org/viralzone/all_by_species/24.html |date=13 June 2010 }}
* [http://www.viprbrc.org/brc/home.do?decorator=flavi Virus Pathogen Database and Analysis Resource (ViPR): Flaviviridae]

{{Baltimore classification}}

{{Taxonbar|from=Q1165479}}
{{Authority control}}

[[Category:Flaviviruses| ]]
[[Category:Rodent-carried diseases]]
[[Category:Flaviviridae]]
[[Category:Virus genera]]