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Exclusive License: Vaccines for dengue and other flaviviruses bioinfo.com |
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. Flaviviruses are named from the yellow fever virus, a type virus for the Flaviviridae family; flavus means yellow in Latin. Yellow fever in turn was named because of its propensity to cause yellow jaundice in victims. [1]. 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 without an intermediate vector arthropod is thought to be unlikely. For example, early tests with yellow fever showed that the disease is not a contagious disease.
[edit] ReplicationFlaviviruses 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. 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. 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. [edit] RNA secondary structure elementsThe (+) sense RNA genome of Flavivirus contain 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.[2][3] 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 contributes to nuclease resistance.[3] It may be related to another hairpin loop identified in the 5'UTR of the Japanese encephalitis virus (JEV) genome [4]. 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-repeate elements and 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 efficienty of the viral genome to 25%.[2]
The final conserved secondary structure is the Cis-acting replication element (CRE) also known as the 3'SL RNA elements is thought to be essential in viral replication by facilitating the formation of a "replication complex".[5] 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.[6] Deletions of the 3' UTR of flaviviruses have been shown to be lethal for infectious clones. [edit] Species
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