Flavivirus

Flavivirus
Flavivirus
A TEM micrograph of the yellow fever virus
Virus classification e -
Virus group: Group IV ((+)ssRNA)
Family: Flaviviridae
Genus: Flavivirus
Type species
Yellow fever virus [1]
Species

(see list in article)

Flavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis.[2]

Flaviviruses are named from the yellow fever virus, the type virus for the family; flavus means yellow in Latin. Yellow fever in turn was named because of its propensity to cause yellow jaundice in victims.[3]

Flaviviruses share a common size (40-65 nm), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single stranded RNA approximately 10,000–11,000 bases), and appearance in the electron microscope.

These viruses are transmitted by the bite from an infected arthropod (mosquito or tick). Human infections with these viruses are typically incidental, as humans are unable to replicate the virus to high enough titres to reinfect arthropods and thus continue the virus life cycle. The exceptions to this are yellow fever and dengue viruses, which still require mosquito vectors, but are well-enough adapted to humans as to not necessarily depend upon animal hosts (although both continue have important animal transmission routes as well).

Other virus transmission routes include handling infected animal carcasses, blood transfusion, child birth and through consumption of unpasteurised milk products. The transmission from animals to humans without an intermediate vector arthropod is thought to be unlikely. For example, early tests with yellow fever showed that the disease is not contagious.

Replication

Flaviviruses have a (+) sense RNA genome and 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 apparatus to synthesise 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. In general the genome encodes 3 structural proteins (Capsid, prM, and Envelope) and 8 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, 2K, NS4B and NS5). The genomic RNA is modified at the 5′ end of positive strand genomic RNA with a cap 1 structure (me7-GpppA-me2)

Cellular RNA cap structures are formed via the action of an RNA triphosphatase, 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.[4] This protein also encodes an 2′-O methyltransferase.

Once translated, the polyprotein is cleaved by a combination of viral and host proteases to release mature polypeptide products. 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 polymerase, responsible for the synthesis of a (-) 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.

RNA secondary structure elements

Flavivirus 3'UTR stem loop IV
RF01415.png
Predicted secondary structure of the Flavivirus 3'UTR stem loop IV
Identifiers
Symbol Flavivirus_SLIV
Rfam RF01415
Other data
RNA type Cis-reg
Domain(s) Flaviviridae
SO 0005836
Flavivirus DB element
RF00525.png
Predicted secondary structure of the Flavivirus DB element
Identifiers
Symbol Flavivirus_DB
Rfam RF00525
Other data
RNA type Cis-reg
Domain(s) Flaviviridae
SO 0000233
Flavivirus 3' UTR cis-acting replication element (CRE)
RF00185.png
Predicted secondary structure of the Flavivirus 3' UTR cis-acting replication element (CRE)
Identifiers
Symbol Flavi_CRE
Alt. Symbols Flavi_pk3
Rfam RF00185
Other data
RNA type Cis-reg
Domain(s) Flaviviridae
SO 0000205
Japanese encephalitis virus (JEV) hairpin structure
RF00465.png
Predicted secondary structure of the Japanese encephalitis virus (JEV) hairpin structure
Identifiers
Symbol JEV_hairpin
Rfam RF00465
Other data
RNA type Cis-reg
Domain(s) Flaviviridae
SO 0000233

The (+) sense RNA genome of Flavivirus contains 5' and 3'untranslated regions (UTRs). The 3'UTRs are typically 0.3-0.5kb in length and contain a number of highly conserved secondary structures which are conserved and restricted to the flavivirus family. The majority of analysis has been carried out using West Nile virus (WNV) to study the function the 3'UTR.

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.[5][6] Some of these secondary structres 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.

SL-II has been suggested to contribute to nuclease resistance.[6] It may be related to another hairpin loop identified in the 5'UTR of the Japanese encephalitis virus (JEV) genome.[7] 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.

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.

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 efficiency of the viral genome to 25%.[5]

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".[8] 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.[9] Deletions of the 3' UTR of flaviviruses have been shown to be lethal for infectious clones.

A conserved hairpin (cHP) structure was later found in several Flavivirus genomes and is thought to direct translation of capsid proteins.[10]

Species

Tick-borne viruses

Mosquito-borne viruses

Viruses with no known arthropod vector

Vaccines

The successful yellow fever 17D vaccine, introduced in 1937, produced dramatic reductions in epidemic activity. Effective killed 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 killed 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. 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. A tetravalent chimeric vaccine that splices structural genes of the four dengue viruses onto a 17D yellow fever backbone is in Phase III clinical testing.[2]

References

  1. ^ "ICTV 2009 MASTER SPECIES LIST VERSION 4". 20 March 2010. http://talk.ictvonline.org/cfs-filesystemfile.ashx/__key/CommunityServer.Components.PostAttachments/00.00.00.12.31/ICTV_2D00_Master_2D00_Species_2D00_List_2D00_2009_5F00_v4.xls 
  2. ^ a b Shi, P-Y (editor) (2012). Molecular Virology and Control of Flaviviruses. Caister Academic Press. ISBN 978-1-904455-92-9. 
  3. ^ http://microbewiki.kenyon.edu/index.php/Flaviviridae Accessed July 22, 2008
  4. ^ Henderson BR, Saeedi BJ, Campagnola G, Geiss BJ (2011) Analysis of RNA binding by the Dengue virus NS5 RNA capping enzyme. PLoS One 6(10):e25795.
  5. ^ a b Chiu WW, Kinney RM, Dreher TW (July 2005). "Control of Translation by the 5′- and 3′-Terminal Regions of the Dengue Virus Genome". J. Virol. 79 (13): 8303–15. doi:10.1128/JVI.79.13.8303-8315.2005. PMC 1143759. PMID 15956576. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1143759. 
  6. ^ a b Pijlman GP, Funk A, Kondratieva N, et al. (December 2008). "A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity". Cell Host Microbe 4 (6): 579–91. doi:10.1016/j.chom.2008.10.007. PMID 19064258. 
  7. ^ Lin KC, Chang HL, Chang RY (May 2004). "Accumulation of a 3′-Terminal Genome Fragment in Japanese Encephalitis Virus-Infected Mammalian and Mosquito Cells". J. Virol. 78 (10): 5133–8. doi:10.1128/JVI.78.10.5133-5138.2004. PMC 400339. PMID 15113895. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=400339. 
  8. ^ Zeng L, Falgout B, Markoff L (September 1998). "Identification of Specific Nucleotide Sequences within the Conserved 3′-SL in the Dengue Type 2 Virus Genome Required for Replication". J. Virol. 72 (9): 7510–22. PMC 109990. PMID 9696848. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109990. 
  9. ^ Shi PY, Brinton MA, Veal JM, Zhong YY, Wilson WD (April 1996). "Evidence for the existence of a pseudoknot structure at the 3' terminus of the flavivirus genomic RNA". Biochemistry 35 (13): 4222–30. doi:10.1021/bi952398v. PMID 8672458. 
  10. ^ Clyde K, Harris E; (2006). "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. doi:10.1128/JVI.80.5.2170-2182.2006. PMC 1395379. PMID 16474125. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1395379. 

External links

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