West Nile virus

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West Nile virus
West Nile Virus Image.jpg
A micrograph of the West Nile Virus, appearing in yellow
Virus classification
Group: Group IV ((+)ssRNA)
Family: Flaviviridae
Genus: Flavivirus
Species: West Nile virus

West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, specifically from the genus Flavivirus which also contain the Zika virusdengue virus, and the yellow fever virus. The West Nile virus is primarily transmitted through mosquitoes, mostly by the Culex species. However, ticks have been found to carry the virus. The primary hosts of WNV are birds, so that the virus remains within a "bird-mosquito-bird" transmission cycle.[1]


WNV, like most other flaviviruses, are enveloped viruses, but have icosahedral symmetry.[2] Their envelopes consist of a protein shell and a lipid membrane. The protein shell is made up of two structural proteins: the glycoprotein E and the small membrane protein M.[3] Protein E serve numerous functions, several of which include receptor binding, viral attachment, and entry into the cell through membrane fusion.[4][3]

The flavivirus lipid membrane has been found to contain cholesterol and phosphatidylserine, but other elements of the membrane have yet to be identified.[5][6] The lipid membrane has many roles in viral infection including acting as signaling molecules and enhancing entrance into the cell[7]. Cholesterol, in particular, plays an integral part to WNV entering a host cell.[8]

Within the viral envelope, the genome is contained within the capsid. The capsid is one of the first proteins created in an infected cell and has been found that that the capsid prevents apoptosis by affecting the Akt pathway.[9] The capsid is a structural protein and its main purpose is to package RNA into the developing viruses.[10]


The genome of the West Nile Virus. Modified after Guzman et al. 2010.[11][12]

WNV is a single stranded, positive sense RNA virus. Its genome is approximately 11,000 nucleotides long and is flanked by a 5' and 3' non-coding stem loop structures.[13] The coding region of the genome encodes for seven nonstructural (NS) proteins , proteins that aren't incorporated into the structure of new viruses, and three structural proteins, proteins that are a part of the virus structure. The WNV genome is first translated into a polyprotein and later cleaved by virus and host proteases into separate proteins (i.e. NS1, C, E).[14]

Structural proteins[edit]

Structural proteins (C, prM/M, E) are capsid, precursor membrane proteins, and envelope proteins respectively.[13] The structural proteins are located at the 5' end of the genome and are cleaved into mature proteins by proteases.

Structural Protein Function
C Capsid protein; encloses the RNA genome, packages RNA into immature virions.[10][15]
prM/M Viruses with M protein are infectious: the presence of M protein allows for the activation of proteins involved in viral entry into the cell. prM (precursor membrane) protein is present on immature virions, by further cleavage by furin to M protein, the virions become infectious.[16]
E A glycoprotein that forms the viral envelope, binds to receptors on the host cell surface in order to enter the cell.[17]

Nonstructural proteins[edit]

Nonstructural proteins consist of NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. These proteins are mainly in viral replication or act as proteases.[15] The nonstructural proteins are located near the 3' end of the genome.

Nonstructural Protein Function
NS1 NS1 is a cofactor for viral replication, specifically for regulation of the replication complex.[18]
NS2A NS2A has a variety of functions: it is involved in viral replication, virion assembly, and inducing host cell death.[19]
NS2B cofactor for NS3 and together forms the NS2B-NS3 protease complex.[15]
NS3 A protease that is responsible for cleaving the polyprotein to produce mature proteins; it can also acts as a helicase.[20]
NS4A NS4A is a cofactor for viral replication, specifically regulates the activity of the NS3 helicase.[21]
NS4B Inhibits interferon signaling.[22]
NS5 The largest and most conserved protein of WNV, NS5 acts as a methyltransferase and a RNA polymerase, though it lacks proofreading properties.[23][15]

Life cycle[edit]

Once WNV has successfully entered the bloodstream of its host, the envelope protein, E, binds to attachment factors on the host cell, glycosaminoglycans.[17] These attachment factors aid entry into the cell, however, binding to primary receptors are also necessary.[24] Primary receptors include DC-SIGN, DC-SIGN-R, and the integrin αvβ3.[25] By binding to these primary receptors, WNV enters the cell through clathrin-mediated endocytosis.[26] As a result of endocytosis, WNV enters the cell in an endosome.

The acidity of the endosome catalyzes the fusion of the endosomal and viral membranes, allowing the genome to be released into the cytoplasm.[27] Translation of the positive single stranded RNA occurs at the endoplasmic reticulum; the RNA is translated into a polyprotein which is then cleaved by NS2B-N23, viral proteases, to produce mature proteins.[28]

In order to replicate its DNA, NS5, a RNA polymerase, forms a replication complex with other nonstructural proteins to produce an intermediary negative sense single stranded RNA; the negative sense strand serves as a template for synthesis of the final positive sense RNA.[24] Once the positive sense RNA has been synthesized, the capsid protein, C, encloses the RNA strands into immature virions.[25] The rest of the virus is assembled along the endoplasmic reticulum and through the Golgi apparatus, and results in non-infectious immature virions.[28] The E protein is then glycosylated and prM is cleaved by furin, a host cell protease, into the M protein, thereby producing an infectious mature virion.[29][28] The mature viruses are then secreted out of the cell.


Phylogenetic tree of West Nile viruses based on sequencing of the envelope gene during complete genome sequencing of the virus[30]

Studies of phylogenetic lineages determined WNV emerged as a distinct virus around 1000 years ago.[31] 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 African 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.[32] 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.[33] A 2007 fatal case in a killer whale in Texas broadened the known host range of West Nile virus to include cetaceans.[34]

The United States virus was very closely related to a lineage 1 strain found in Israel in 1998. Since the first North American cases in 1999, the virus has been reported throughout the United States, Canada, Mexico, the Caribbean, and Central America. There have been human cases and equine cases, and many birds are infected. The Barbary macaque, Macaca sylvanus, was the first nonhuman primate to contract WNV.[35] Both the United States and Israeli strains are marked by high mortality rates in infected avian populations; the presence of dead birds—especially Corvidae—can be an early indicator of the arrival of the virus.


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