Virology, Pathology, and Clinical Manifestations of West Nile Virus Disease

West Nile virus (WNV) causes epidemics of febrile illness, meningitis, encephalitis, and flaccid paralysis.Since it was first detected in New York City in 1999, and through 2004, >16,000 WNV disease cases have been reported in the United States.Over the past 5 years, research on WNV disease has expanded rapidly.This review highlights new information regarding the virology, clinical manifestations, and pathology of WNV disease, which will provide a new platform for further research into diagnosis, treatment, and possible prevention of WNV through vaccination. T he impressive spread of West Nile virus (WNV) in theWestern Hemisphere after its detection in 1999 during an outbreak of encephalitis in New York City has caused >16,000 human disease cases and >660 deaths in North America.Research on the signs, symptoms, and pathogenesis of WNV disease has greatly intensified in the past 5 years.The number of recognized cases of flaccid paralysis due to WNV infection has increased substantially, and research into prognosis and possible therapy has expanded.Genetic variation of the virus has been further characterized and continues to be explored.The pathology and pathogenesis of WNV disease have been described more completely than ever before.Several strategies are being pursued to develop effective vaccines to prevent WNV disease.This article highlights new information about the virology, clinical manifestations, laboratory diagnosis, pathology, and prognosis of WNV illness in humans.The expanded knowledge about WNV disease provides a new platform for future development of diagnostic tests, therapy, and vaccine development. Characteristics of West Nile VirusWNV is an arbovirus in the family Flaviridae.Its spherical, enveloped capsid has a diameter of ≈50 nm and contains single-stranded RNA that encodes the capsid (C), envelope (E), and premembrane (prM) proteins, as well as 7 nonstructural proteins that likely contribute to viral replication.The virus has 2 genetic lineages: lineage 1 strains are found in North America, Europe, Africa, Asia, and Australia; lineage 2 strains have been isolated only in sub-Saharan Africa and Madagascar.Lineage 1 strains have been further divided into 4 clades: Kunjin, Indian, A, and B (which includes an Indian isolate) (1).The isolates in clade B, which includes strains from the United States, are all virulent in mice; lineage 2 and other clades in lineage 1 comprise both virulent and attenuated strains (1).Differences in pathogenicity may be related to nucleotides that code for specific regions in the prM, E, or nonstructural proteins of the virus (1,2).WNV strains from the United States are closely related to strains from Israel, with 99.7% homology in nucleotide sequences, indicating that the strains in the United States almost certainly originated from the Middle East (3).The strain isolated in New York in 1999 is more virulent in American crows (Corvus brachyrynchos) than strains from Kenya and Australia (Kunjin virus, a subtype of WNV), and both the New York strain and the Kenyan strain experimentally killed house sparrows whereas the Australian strain did not (4).Two genetic variants of the North American WNV strain were isolated in Texas in 2002; the major variant differed from the New York 1999 isolate by 0.18% of nucleotides, and the minor variant by 0.35% (1).The 2 variants differed from each other by 0.5% of nucleotides, and their neuroinvasiveness in mice was similar to that of the New York 1999 isolate.In 2003, attenuated WNV