Flaviviridae
By Maria Raquel Kronen

Yellow Fever
Dengue
Japanese Encephalitis
St. Louis Encephalitis
West Nile Virus
Hepatitis C
Hepatitis G

Wednesday March 12, 2008

 

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The Basics

Introduction
The word “flavi” is latin for yellow because one of the most famous flaviviruses is Yellow Fever Virus.  Viruses in the flavivirus family are all single-stranded RNA viruses with linear non-segmented genomes.  Viruses in this family are considered positive (+) sense because proteins are made directly from the template strand of RNA which is present in the viral capsid.  Production of a complementary RNA strand is not necessary for viruses in this family to produce protein. The genome of these viruses are on average 11,000 nucleotides long - they encode around 10 genes.  The capsid of viruses in this family are icosahedral shaped and around the viral capsid a spherical shaped envelope is present.  The capsids are approximately 40-50 nanometers in diameter and are composed of a single type of capsid protein.

Molecular Biology
Genome
Unlike cellular mRNA, the genome of Flavivirus lacks a poly-A tail. However, a type I cap does sit on the 5 end and type II caps have been found in the RNA of infected cells. The Flaviviridae genome is composed of only one single open reading frame (ORF) and on both ends of this ORF non-structural regions of approximately 100 nucleotides exist. 5 non-coding regions are not highly conserved throughout different Flaviviridae species and 3 non-coding regions tend to be highly variable between the viruses that are transmitted by mosquitoes and the viruses that are transmitted by ticks. The Flaviviridae genome is infectious. In Flaviviruses structural genes are found at the 5 of the genome and non-structural genes are encoded at the 3 end of the genome. This organization allows the virus to maximize production of structural genes, since viral assembly requires more structural proteins to be made than non-structural proteins.

Replication
Replication of Flaviviruses takes place in the cytoplasm. Flavivirus cannot replicate in the nucleus because, like most other RNA viruses, it uses the host cell's RNA dependant RNA polymerase to replicate. Primarily, the virus will make a full length copy of the complementary, minus strand genome. This complementary genome then serves as a template strand for further replication. Over the course of replication, about ten plus strands accumulate for each negative template strand. It has been shown that in order for Flaviviridae viruses to replicate successfully they must have complementary binding regions on both the 3 and the 5 ends of the genome which allow cyclization of the genome to occur.

Translation
Transcription is initiated by ribosomal scanning for an internal ribosome binding site (IRES). The type I cap on the 5' end is necessary for stabilization of the ribosome on the RNA (in all viruses except for dengue). After the ribosome binds to the genome a single poly-protein is translated and then is cleaved into at least ten smaller proteins by peptidase, protease and other currently unknown enzyme. One fourth of the poly-protein is composed of structural proteins, while the other three fourths are non-structural proteins.

Proteins
Flaviviridae has three structural proteins as follows: C/V2 are the capsid proteins, M/V1 are the matrix proteins and E/V3 are the envelope proteins and glycoproteins. Flaviviridae encodes seven non-structural proteins whose functions are not entirely designated by include protease, helicase, replicase and virion maturation.

Epidemiology
Transmission
Viruses in the Flavi genera are transmitted by arthropods, mainly mosquitoes and ticks. Flaviviruses that are transmitted by arthropods are known as Group B Arboviruses. "Arboviruses" (viruses transmitted by arthropods) include Yellow Fever Virus, Dengue Fever Virus, and Japanese Encephalitis Virus (see list below for full inclusion). Viruses in the Hepaci genera, Hepatitis C and Hepatitis G, are transmitted parenterally (through blood) as well as sexually and vertically (from mother to child).

Prevention
Vaccines exist for both Yellow Fever Virus and Japanese Encephalitis. Both vaccines are inactivated and have proved highly efficacious in labs and clinics. For more information about vaccines see Timeline. Otherwise the best ways to prevent infection with arboviruses are behavioral, such as using mosquito nets, bug repellent and protective clothing. With hepatitis viruses, behavioral preventative measures such as protected sex, refraining from injection drug use, and proper disposal of needles is suggested. Any blood or products that have come into contact with blood should be handled with utmost caution.

Genera
Genus Flavi
Dengue Fever Virus 1-4 – fever, rash, arthralgia, myalgia
West Nile Fever Virus - fever, rash, arthralgia, myalgia
Yellow Fever Virus - fever, hemorrhage, jaundice
St. Louis Encephalitis Virus – encephalitis  
Japanese Encephalitis Virus – encephalitis  
Murray Valley Encephalitis Virus – encephalitis
Tick-borne Encephalitis Virus – encephalitis
Kunjin Encephalitis Virus – encephalitis
Rocio Encephalitis Virus – encephalitis
Russian Spring Summer Encephalitis Virus – encephalitis
Negeishi Virus – encephalitis
Kyasanur Forest Virus - fever, hemorrhage, encephalitis
Omsk Hemorrhagic Fever Virus - fever, hemorrhage
Powassan Virus - encephalitis
Louping Ill Virus - encephalitis (also infects sheep)
Rio Bravo Virus 1-7
Tyuleniy Virus
Ntaya Virus
Uganda S Virus/Zika Virus – acute viral fever
Modoc Virus – encephalitis

Genus Pesti
Bovine diarrhea 1-3 – known to infect animals only

Genus Hepaci
Hepatitis C Virus - hepatitis
Hepatitis G Virus – hepatitis

Memorable Notes
1) Flaviviruses translate a single poly-protein
2) 5 end = structural genes
3) 3 ends = non-structural genes
4) Flaviviruses produce no sub-genomic RNA
5) Arbo Flaviviruses are Group B
6) Hepatitis C is a Flavivirus
7) Flaviviruses cause encephalitis
8) Flaviviruses cause hemorrhagic fever
9) When traveling get your Yellow Fever vaccination!
10) When traveling to endemic areas get your Japanese Encephalitis vaccination!

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Bless you! Take care of that viral infection!