Elsevier

The Lancet Neurology

Volume 6, Issue 2, February 2007, Pages 171-181
The Lancet Neurology

Review
West Nile virus

https://doi.org/10.1016/S1474-4422(07)70030-3Get rights and content

Summary

West Nile virus is a mosquito-borne flavivirus originally isolated in 1937 from the blood of a febrile woman in the West Nile province of Uganda. The virus is widely distributed in Africa, Europe, Australia, and Asia, and, since 1999, it has spread rapidly throughout the western hemisphere, including the USA, Canada, Mexico, and the Caribbean and into parts of Central and South America. Before 1994, outbreaks of West Nile virus were sporadic and occurred primarily in the Mediterranean region, Africa, and east Europe. Since 1994, outbreaks have occurred with a higher incidence of severe human disease, particularly affecting the nervous system. In North America, the virus has caused meningitis, encephalitis, and poliomyelitis, resulting in significant morbidity and mortality. The goal of this Review is to highlight recent advances in our understanding of West Nile virus virology, ecology, clinical disease, diagnosis, and development of potential vaccines and antiviral therapies.

Introduction

Many members of the genus Flavivirus within the family Flaviviridae cause substantial human disease, including West Nile, dengue, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus.1 Neuroinvasiveness is a common feature of flavivirus infections where Culex mosquitoes are the predominant mosquito vector. Since 1999, about 19 525 cases of West Nile disease have been reported in the USA, of which 8 606 (44%) caused neuroinvasive disease with 771 fatalities (3·9% of all; 9·0 % of neuroinvasive disease; table).2 The 2002–03 epidemics were the largest outbreaks of meningitis or encephalitis ever reported in the western hemisphere, making West Nile virus the dominant vector-borne viral pathogen in North America. Seroprevalence varied from 0·3% in Alberta, Canada, to 9·5% in Nebraska, with even higher rates in local areas following the large scale outbreak in 2003.3, 4 In North Dakota, USA, in 2003, blood donor screening suggested that 735 000 individuals were infected with West Nile virus, with 0·4% of these presenting with neuroinvasive disease.5 Interestingly, almost no morbidity and mortality have been recognised in human beings, equines, and birds in Latin America and South America, although two equine cases were recently reported in Argentina.6 The reasons for this are not clear but hypotheses include protection by antigenically cross-reactive flaviviruses,7 decreased virulence of the circulating virus, high biodiversity in tropical regions leading to a dilution effect,8 and decreased intensity of surveillance and diagnostic efforts.

Section snippets

West Nile virus ecology

West Nile virus is maintained worldwide in an enzootic cycle, transmitted primarily between avian hosts and mosquito vectors. Mosquitoes of the genus Culex are implicated as the predominant vectors in the enzootic cycle throughout the range of the virus' distribution.9 The predominant mode of perpetuation of the virus in a temperate environment over adverse seasons is likely to be by vertically infected diapausing (ie, physiologically enforced dormancy between periods of activity) adult

Molecular epidemiology

Phylogenetic analyses of global West Nile virus strains have revealed two distinct lineages (I and II). Lineage I strains are commonly involved in human and equine outbreaks. Phylogenetic analyses of West Nile virus isolated from the USA indicates that the virus remains highly conserved genetically and was successfully introduced only once into North America. A single conserved aminoacid change in the envelope gene (V159A) is shared by most strains isolated since 2002 (North American dominant)24

Basic virology

Cryoelectron microscopy showed that virions of West Nile virus have icosahedral symmetry of 50 nm in diameter, with no surface projections or spikes (figure 1).27 The outermost layer contains the viral envelope and membrane proteins embedded in a lipid bilayer, forming the envelope of the virion. Inside the envelope is the nucleocapsid core, which consists of multiple copies of the capsid protein and genomic RNA. The West Nile virus genome is a single-stranded RNA of plus-sense polarity (ie,

Host proteins and flavivirus resistance

Host proteins have important roles in West Nile virus replication. Translation elongation factor alpha (EF-1α) binds specifically to the 3′ stem-loop of the plus-sense genomic RNA,28 wherease host proteins TIAR and TIA-1 bind to the 3′ stem-loop of the minus-sense RNA.29 The functions of such host–protein binding to viral RNA are unclear. The Src family kinase c-Yes was recently reported to be important for maturation of West Nile virus particles.30 Inbred mouse strains exhibit significant

Evasion of host innate immune response

Flavivirus non-structural proteins suppress host antiviral immune responses; however, the molecular details are unknown. Expression of the dengue virus-2 NS4B and, to a lesser extent, NS2A and NS4A proteins, results in down-regulation of interferon-β-stimulated gene expression.34 The inhibition could be mediated by the 125 N-terminal aminoacid residues of dengue virus-2 NS4B protein.35 During West Nile virus infection, the host response limits viral spread through the activation of the

Clinical presentation

Most individuals infected with West Nile virus are asymptomatic. Symptoms may develop in 20–40% of people with West Nile virus infection.41, 42 The incubation period is 2–14 days before symptom onset. Most patients that are symptomatic present with flu-like symptoms (West Nile fever). West Nile virus is characterised by fever, headache, malaise, myalgia, fatigue, skin rash, lymphadenopathy, vomiting, and diarrhoea.43 Less than 1% of infected individuals develop severe neuroinvasive diseases, a

Clinical laboratory features

To diagnose West Nile virus infection, serum from patients should be tested for IgM antibodies against the virus (usually by ELISA), which are usually indicative of a recent West Nile virus infection. Blood samples that are collected between the eighth and 21st day after onset likely to give the best yield. IgM antibodies are only detectable 8 days post-symptom onset in some patients.74, 75 Thus, there may be a negative result from a blood sample obtained before the eighth day after symptom

Neuropathology and pathogenesis of clinical syndromes

West Nile virus is thought to initially replicate in dendritic cells after being bitten by an infected mosquito. The infection then spreads to regional lymph nodes and into the bloodstream.2 The way in which the virus invades the nervous system is still unknown; retrograde transport along peripheral nerve axons has been proposed.70, 78 On the basis of animal models, a Toll-like receptor-dependent inflammatory response could be involved in brain penetration of the virus and neuronal injury.79

Diagnosis

The diagnosis of West Nile virus paralysis should be considered whenever clinical presentation of viral meningitis or encephalitic and acute asymmetric paralysis with normal sensory examination occurs during the seasons when mosquito-borne diseases might occur. Absence of viral prodrome does not exclude the diagnosis.57, 65 Electrophysiological studies and neuroimaging can be helpful. A definitive diagnosis for neuroinvasive diseases usually requires a positive IgM antibody test from the serum

Vaccine development

Human vaccines for flavivirus infections are currently available only for yellow fever, Japanese encephalitis, and tick born encephalitis.1 Because the premembrane and envelope proteins are highly antigenic and elicit strong and long-lasting immune responses, multiple approaches have been explored to deliver these antigens into animals for vaccine development. The first approach is based on chimeric viruses delivering West Nile virus antigens. The yellow fever 17D vaccine strain, which has been

Antiviral therapy

There is no specific regime currently available for treatment of flavivirus infections. Although several compounds have been reported to inhibit recombinant West Nile virus enzymes or to suppress virus in cell culture, few of them have shown in vivo efficacy. Antibody-based therapy has yielded the most promising results. Passive administration of monoclonal antibodies has previously shown prevention and alleviation of St Louis encephalitis,112 Japanese encephalitis,113 and encephalitis caused

Conclusions

Improvement in our understanding of flavivirus virology, ecology, and pathogenesis will substantially contribute to the prevention and treatment of flavivirus infections. For example, crystallographic studies have shown that envelope proteins undergo a sequential structural change during the fusion-activating transition.124 Small-molecule inhibitors could be developed to block the structural switch that is essential for viral–host membrane fusion. The findings that flavivirus proteins

Search strategy and selection criteria

References for this Review were identified by searches of PubMed using the terms “West Nile virus” and “flavivirus” from 1950 to March 2006. Additional references and book chapters that were cited in relevant papers were also used. Abstracts from conferences were also included. Only references in English were used. References were selected on the bases of originality and relevance.

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