Flavivirus Explained

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Flavivirus is a genus of positive-strand RNA viruses 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 viruses which may cause encephalitis,[1] as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV).[2] While dual-host flaviviruses can infect vertebrates as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods.[3]

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.[4]


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 titers to reinfect the arthropods needed to continue the virus lifecycle – 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, child birth and consumption of 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.



Flaviviruses are enveloped and spherical and have icosahedral geometries with a pseudo T=3 symmetry. The virus particle diameter is around 50 nm.


Flaviviruses have positive-sense, single-stranded RNA genomes which are non-segmented and around 10–11 kbp in length.[6] In general, the genome encodes three structural proteins (Capsid, prM, and Envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5).[7] The genomic RNA is modified at the 5′ end of positive-strand genomic RNA with a cap-1 structure (me7-GpppA-me2).

Life cycle

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. This feature allows the virus to exploit cellular apparatuses to synthesize both structural and non-structural proteins, during 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.[7]

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 ATP or GTP and enhanced by S-adenosyl methionine.[8] This protein also encodes a 2′-O methyltransferase.Once translated, the polyprotein is cleaved by a combination of viral and host proteases to release mature polypeptide products.[9] Nevertheless, cellular post-translational modification is dependent on the presence of a poly-A tail; therefore this process is not host-dependent. Instead, the polyprotein contains an autocatalytic feature which automatically releases the first peptide, a virus specific enzyme. This enzyme is then able to cleave the remaining polyprotein 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 progeny RNA.

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.

A G protein-coupled receptor kinase 2 (also known as ADRBK1) appears to be important in entry and replication for several viruses in Flaviviridae.[10]


RNA secondary structure elements

The positive sense RNA genome of Flavivirus contains 5' and 3' untranslated regions (UTRs).


See main article: Flavivirus 5' UTR.

The 5'UTRs are 95–101 nucleotides long in Dengue virus.[11] 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.[12] SLA is likely to act as a promoter, and is essential for viral RNA synthesis.[13] [14] 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.[15]




SL-II has been suggested to contribute to nuclease resistance.[17] It may be related to another hairpin loop identified in the 5'UTR of the Japanese encephalitis virus (JEV) genome.[18] 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.



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".[19] 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.[20] Deletions of the 3' UTR of flaviviruses have been shown to be lethal for infectious clones.

Conserved hairpin cHP


The role of RNA secondary structures in sfRNA production

Subgenomic flavivirus RNA (sfRNA) is an extension of the 3' UTR and has been demonstrated to play a role in flavivirus replication and pathogenesis.[22] sfRNA is produced by incomplete degradation of genomic viral RNA by the host cells 5'-3' exoribonuclease 1 (XRN1).[23] As the XRN1 degrades viral RNA, it stalls at stemloops formed by the secondary structure of the 5' and 3' UTR.[24] 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[25] (2) inhibition of XRN1 and Dicer activity to modify RNAi pathways that destroy viral RNA[26] (3) modification of the viral replication complex to increase viral reproduction.[27] Overall, sfRNA is implied in multiple pathways that compromise host defenses and promote infection by flaviviruses.


The flaviviruses can be divided into two clades: one with the vector-borne viruses and the other with no known vector.[28] The vector clade in turn can be subdivided into a mosquito-borne clade and a tick-borne clade. These groups can be divided again.[29]


The tick-borne viruses also form two distinct groups: one is associated with seabirds and the other – the tick-borne encephalitis complex viruses – is associated primarily with rodents.


It seems likely that tick transmission may have been derived from a mosquito-borne group.[30]

A partial genome of a flavivirus has been found in the sea spider Endeis spinosa.[31] The sequences are related to those in the insect-specific flaviviruses. It is not presently clear how this sequence fits into the evolution of this group of viruses.Estimates of divergence times have been made for several of these viruses.[32] 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.

Phylogenetic studies of the West Nile virus have shown that it emerged as a distinct virus around 1000 years ago.[33] 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.[34] 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.[35] A 2007 fatal case in a killer whale in Texas broadened the known host range of West Nile virus to include cetaceans.[36]




In the genus Flavivirus there are 53 defined species:[38]

Sorted by vector




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 vaccines 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.[39] [40] Dengvaxia is approved in five countries.[41]

Further reading

External links

Notes and References

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  2. McLean. Breeanna J.. Hobson-Peters. Jody. Webb. Cameron E.. Watterson. Daniel. Prow. Natalie A.. Nguyen. Hong Duyen. Hall-Mendelin. Sonja. Warrilow. David. Johansen. Cheryl A.. Jansen. Cassie C.. van den Hurk. Andrew F.. Beebe. Nigel W.. Schnettler. Esther. Barnard. Ross T.. Hall. Roy A.. A novel insect-specific flavivirus replicates only in Aedes-derived cells and persists at high prevalence in wild Aedes vigilax populations in Sydney, Australia. Virology. 2015. 486. 272–283. 10.1016/j.virol.2015.07.021. 26519596. free.
  3. Elrefaey. Ahmed ME. Abdelnabi. Rana. Rosales Rosas. Ana Lucia. Wang. Lanjiao. Basu. Sanjay. Delang. Leen. September 2020. Understanding the Mechanisms Underlying Host Restriction of Insect-Specific Viruses. Viruses. en. 12. 9. 964. 10.3390/v12090964. 32878245. 7552076. free.
  4. The earliest mention of "yellow fever" appears in a manuscript of 1744 by 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:

    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.

  5. Bekal S, Domier LL, Gonfa B, McCoppin NK, Lambert KN, Bhalerao K . A novel flavivirus in the soybean cyst nematode . Journal of General Virology. 10.1099/vir.0.060889-0 . 24643877 . 95 . Pt 6 . 1272–1280. 2014 . free .
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  20. Shi PY, Brinton MA, Veal JM, Zhong YY, Wilson WD . Evidence for the existence of a pseudoknot structure at the 3' terminus of the flavivirus genomic RNA . Biochemistry . 35 . 13 . 4222–30 . April 1996 . 8672458 . 10.1021/bi952398v .
  21. Clyde K, Harris E . RNA Secondary Structure in the Coding Region of Dengue Virus Type 2 Directs Translation Start Codon Selection and Is Required for Viral Replication . J Virol . 80 . 5. 2170–2182 . 2006 . 16474125 . 10.1128/JVI.80.5.2170-2182.2006 . 1395379.
  22. Bidet. Katell. Garcia-Blanco. Mariano A.. 2014-09-01. Flaviviral RNAs: weapons and targets in the war between virus and host. Biochemical Journal. en. 462. 2. 215–230. 10.1042/BJ20140456. 0264-6021. 25102029.
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