TABLE OF CONTENTS

1……INTRODUCTION

2…....STRUCTURE OF FLAVIVRUS

3……LIFE CYCLE

4…....REPLICATION OF FLAVIVIRUSE

5…....EVOLUTION

6……SPECIES

7….... RNA SECONDARY STRUCTURE

ELEMENTS

8……VACCINES

9……REFERENCES
 FLAVIVIRUSES

1 INTRODUCTION:
It is the family of positive single stranded, enveloped RNA viruses.
They are found in arthropods and can occasionally infect humans.
Members of this family belongs to a single genus, Flavirus, and cause
widespread motility throughout the world. Some flaviviruses are
transmitted by mosquitoes and are transmitted by ticks and are
responsible for hemorrhagic diseases.

2 STRUCTURE OF FLAVIVIRUSES:

Viruses in Flavivirus are enveloped, with icosahedral and spherical

geometries. The diameter is around 50 nm. Genomes are linear
positive-sense RNA and non-segmented, around 10–11kb in length.
[1]

3 LIFE CYCLE:
Entry into the host cell is achieved by attachment of the viral
envelope protein E to host receptors,. Replication follows the positive
stranded RNA virus replication model. Positive stranded RNA virus
transcription is the method of transcription. Humans, mammals,
mosquitoes, and ticks serve as the natural host. Transmission routes
are zoonosis and bite.
4 REPLICATION OF FLAVIVIRUSES:
The virus enters host cells by receptor-mediated endocytosis and the
~11 kb positive-sense RNA genome gains entry into the cytoplasm by
viral glycoprotein-mediated membrane fusion. Flavivirus replication
begins when the genome is recognized as messenger RNA and
translated by host cell machinery to yield a single polyprotein. The
polyprotein is co- and post-translationally cleaved by viral and
cellular proteases into 10 gene products. The structural proteins
capsid, precursor membrane and envelope are incorporated into the
virion, whereas the non-structural proteins NS1, NS2A, NS2B, NS3,
NS4A, NS4B and NS5 serve to coordinate the intracellular aspects of
virus replication, assembly and modulation of host defense
mechanisms. NS1 is essential for virus replication and inhibition of
complement-mediated immune response. NS3 contains serine
protease, Nucleoside 5’ triphosphatase (NTPase), RNA helicase, and
5’ RNA triphosphatase (RTPase) activities, while NS2B serves as a
cofactor for the protease activity of NS3. NS5 contains
methyltransferase and RNA-dependent RNA polymerase (RdRp)
domains required for genome replication and capping of nascent
RNA. Three non-enzymatic, integral membrane proteins NS2A,
NS4A and NS4B are poorly understood. NS2A is required for virus
replication and assembly. NS4A induces membrane rearrangement
and autophagy to enhance viral replication, whereas NS4B modulates
host immune response by suppressing the α/β interferon signaling and
the helicase activity of NS3.
5 EVOLUTION:
The genus flavivirus include 53 recognized species, many of which
are several pathogens and several other viruses yet to be documented
as species. On the bases of phylogenetic evidences and taking into the
account their own vectors and natural vertebrate hosts, the species are
divided into ecological distinguishable groups that form
phylogenetically distinct lineages. The flaviviruses can be divided
into 2 clades: one with the vector borne viruses and the other with no
known vector.[5] The vector clade in turn can be subdivided into a
mosquito-borne clade and a tick-borne clade. These groups can be
divided again.[6]

It seems likely that tick transmission may have been derived from a
mosquito-borne group.[7]

A partial genome of a flavivirus has been found in the sea spider  

endies spinosa.[8] 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.[9]
Estimates of divergence times have been made for several of these
viruses. 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.[10]. 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. 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  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. A 2007
fatal case in a killer whale in Texas broadened the known host
range of West Nile virus to include cetaceans.
Omsk haemorrhagic fever virus appears to have evolved within the
last 1000 years.[38] 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 species which is highly susceptible to this virus was introduced
into this area in the 1930s.

6 SPECIES:
The following is a list of species:
Tick-borne viruses
Mammalian 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

Mosquito-borne viruses:

 Without known vertebrates:

o Aedes galloisi flavivirus
o Barkedji virus
o Calbertado virus
o Chaoyang virus
o Culex flavivirus
o Culex theileri flavivirus
  Spanish Culex flavivirus
 Wang Thong virus
o Culiseta flavivirus
o Donggang virus
o Hanko virus
 Ochlerotatus caspius flavivirus
 Spanish Ochlerotatus flavivirus
o Ilomantsi virus
o Kamiti River virus
o Lammi virus
o Marisma mosquito virus
o Nakiwogo virus
o Nhumirim virus
o Nienokoue virus
o Nounané virus
o Palm Creek virus
o Panmunjeom flavivirus
o Quang Binh virus
 Yunnan Culex flavivirus
 Aroa virus group
o Aroa virus (AROAV)
o Bussuquara virus (BSQV)
o Iguape virus (IGUV)
o Naranjal virus (NJLV)
  Dengue virus group
o Dengue virus (DENV)
o Kedougou virus (KEDV)

7 RNA SECONDARY STRUCTURE ELEMENTS:

The (+) sense RNA genome of Flavivirus contains 5' and

3' untranslated regions (UTRs).
5'UTR[edit]
The 5'UTRs are 95–101 nucleotides long in Dengue virus.[2] 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. SLA is
likely to act as a promoter, and is essential for viral RNA
synthesis. 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.
3'UTR
The 3'UTRs are typically 0.3–0.5 kb 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. 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.
 SL-II
SL-II has been suggested to contribute to nuclease resistance. It may
be related to another hairpin loop identified in the 5'UTR of
the Japanese encephalitis virus (JEV) genome. 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.
 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.
 DB1/DB2
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%.
 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". 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. Deletions of the 3' UTR of flaviviruses
have been shown to be lethal for infectious clones. Subgenomic
flavivirus RNA (sfRNA) is an extension of the 3' UTR and has been
demonstrated to play a role in flavivirus replication and pathogenesis.
[23]
 sfRNA is produced by incomplete degradation of genomic viral
RNA by the host cells 5'-3' exoribonuclease 1 (XRN1).[24] As the
XRN1 degrades viral RNA, it stalls at stemloops formed by the
secondary structure of the 5' and 3' UTR.[1] 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 [2] inhibition of XRN1 and Dicer activity to modify RNAi
pathways that destroy viral RNA [3](3) modification of the viral
replication complex to increase viral reproduction. [4] Overall, sfRNA
is implied in multiple pathways that compromise host defenses and
promote infection by flaviviruses.

8 VACCINES:
The very successful yellow fever 17D vaccine, introduced in 1937,
produced dramatic reductions in epidemic activity.
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.
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. Dengvaxia is
approved in five countries.

9 REFERENCES:

1. (2) gasaki, Tomoko; Torres, Shessy; Floden, Nadia; Melian,

Ezequiel Balmori; Edmonds, Judy; Dong, Hongping; Shi, Pei-
Yong (1 November 2010). "RNA Structures Required for
Production of Subgenomic Flavivirus RNA". Journal of
Virology. 84(21): 11407–11417. doi:10.1128/JVI.01159-
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2. ^ Chang, Ruey-Yi; Hsu, Ta-Wen; Chen, Yen-Lin; Liu, Shu-Fan;
Tsai, Yi-Jer; Lin, Yun-Tong; Chen, Yi-Shiuan; Fan, Yi-Hsin (27
September 2013). "Japanese encephalitis virus non-coding RNA
inhibits activation of interferon by blocking nuclear
translocation of interferon regulatory factor 3". Veterinary
Microbiology. 166 (1–2): 11–
21. doi:10.1016/j.vetmic.2013.04.026. PMID 23755934.
3. ^ Moon, Stephanie L.; Anderson, John R.; Kumagai, Yutaro;
Wilusz, Carol J.; Akira, Shizuo; Khromykh, Alexander A.;
Wilusz, Jeffrey (1 November 2012). "A noncoding RNA
produced by arthropod-borne flaviviruses inhibits the cellular
exoribonuclease XRN1 and alters host mRNA
stability". RNA. 18 (11): 2029–
2040. doi:10.1261/rna.034330.112. ISSN 1355-8382. PMC 34
79393. PMID 23006624.
4. ^ Clarke, B. D.; Roby, J. A.; Slonchak, A.; Khromykh, A. A. (3
August 2015). "Functional non-coding RNAs derived from the
flavivirus 3′ untranslated region". Virus Research. Special
Issue: Functions of the ends of positive strand RNA virus
genomes. 206: 53–
61. doi:10.1016/j.virusres.2015.01.026. PMID 25660582.
5. ^ Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N, Cropp CB
(1998). "Phylogeny of the genus Flavivirus". J Virol. 72(1):
73–83. doi:10.1128/JVI.72.1.73-83.1998. PMC 109351. PMID 
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6. ^ Gaunt MW, Sall AA, de Lamballerie X, Falconar AK,
Dzhivanian TI, Gould EA (2001). "Phylogenetic relationships
of flaviviruses correlate with their epidemiology, disease
association and biogeography". J Gen Virol. 82 (8): 1867–
1876. doi:10.1099/0022-1317-82-8-1867. PMID 11457992.
7. ^ Cook S, Holmes EC (2006). "A multigene analysis of the
phylogenetic relationships among the flaviviruses (Family:
Flaviviridae) and the evolution of vector transmission". Arch
Virol. 151 (2): 309–325. doi:10.1007/s00705-005-0626-
6. PMID 16172840.
8. ^ Conway MJ (2015). "Identification of a flavivirus sequence in
a marine arthropod". PLOS ONE. 10 (12):
e0146037. Bibcode:2015PLoSO..1046037C. doi:10.1371/journ
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9. ^ Moureau, Gregory; Cook, Shelley; Lemey, Philippe;
Nougairede, Antoine; Forrester, Naomi L.; Khasnatinov,
Maxim; Charrel, Remi N.; Firth, Andrew E.; Gould, Ernest A.;
De Lamballerie, Xavier (2015). "New Insights into Flavivirus
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 TABLE OF CONTENTS

1 INTRODUCTION
2 STRUCTURE OF FLAVIRUS
3
4