Abstract
West Nile virus (WNV) is a member of the genus Flavivirus in the family Flaviviridae. Flaviviruses replicate in the cytoplasm of infected cells and modify the host cell environment. Although much has been learned about virion structure and virion-endosomal membrane fusion, the cell receptor(s) used have not been definitively identified and little is known about the early stages of the virus replication cycle. Members of the genus Flavivirus differ from members of the two other genera of the family by the lack of a genomic internal ribosomal entry sequence and the creation of invaginations in the ER membrane rather than double-membrane vesicles that are used as the sites of exponential genome synthesis. The WNV genome 3' and 5' sequences that form the long distance RNA-RNA interaction required for minus strand initiation have been identified and contact sites on the 5' RNA stem loop for NS5 have been mapped. Structures obtained for many of the viral proteins have provided information relevant to their functions. Viral nonstructural protein interactions are complex and some may occur only in infected cells. Although interactions between many cellular proteins and virus components have been identified, the functions of most of these interactions have not been delineated.
Highlights
West Nile virus (WNV) is maintained in nature in a mosquito-bird transmission cycle and has recently become endemic in the Western hemisphere
Structural analysis of the flavivirus RNA-dependent-RNA polymerases (RdRps) domains revealed two conserved cavities in thumb subdomains and mutation of amino acids in these cavities in either a dengue infectious clone or a recombinant protein identified one residue (Lys765) in cavity A that was critical for virus replication but did not affect RdRp activity, three residues (Lys330, Trp859 and Ile863) that are required for initiation of RNA synthesis and one (Lys330) that interacts with NS3 in cavity B [179]
The degree of decrease in efficiency of plus strand RNA synthesis and virus production correlated with the degree of decrease in efficiency of in vitro protein binding, but minus strand RNA levels were similar for the different mutant RNAs suggesting that the interaction between T cell-restricted intracellular antigen-1 (TIA)-1/TIAR and the 3' terminal stem loop (SL) of the WNV minus strand RNA facilitates exponential genome RNA synthesis from the minus-strand template
Summary
West Nile virus (WNV) is maintained in nature in a mosquito-bird transmission cycle and has recently become endemic in the Western hemisphere. Serial passage of WNV or Japanese encephalitis virus isolates in human adenocarcinoma (SW13) cells produced virus with a small plaque phenotype, an increased affinity for heparin-sepharose and attenuated neuroinvasiveness in mouse models of flavivirus encephalitis [13] These results were interpreted to indicate that the passage variants had an altered interaction with surface glycosaminoglycans involved in attachment or entry. This association may help to protect the incoming viral genome from cellular nucleases and RNA sensors as well as provide a “scaffold” on the outer surface of endosomes for the genome as it switches back and forth between initial rounds of translation and replication In support of this hypothesis, flavivirus C proteins were reported to be able to function as RNA chaperones [34,35]
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