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Exclusion of West Nile virus superinfection through RNA replication.

Abstract
Superinfection exclusion is the ability of an established viral infection to interfere with a second viral infection. Using West Nile virus (WNV) as a model, we show that replicating replicons in BHK-21 cells suppress subsequent WNV infection. The WNV replicon also suppresses superinfections of other flaviviruses but not nonflaviviruses. Mode-of-action analysis indicates that the exclusion of WNV superinfection occurs at the step of RNA synthesis. The continuous culturing of WNV in the replicon-containing cells generated variants that could overcome the superinfection exclusion. The sequencing of the selected viruses revealed mutations in structural (prM S90R or envelope E138K) and nonstructural genes (NS4a K124R and peptide 2K V9M). Mutagenesis analysis showed that the mutations in structural genes nonselectively enhance viral infection in both naïve and replicon-containing BHK-21 cells; in contrast, the mutations in nonstructural genes more selectively enhance viral replication in the replicon-containing cells than in the naïve cells. Mechanistic analysis showed that the envelope mutation functions through the enhancement of virion attachment to BHK-21 cells, whereas the 2K mutation (and, to a lesser extent, the NS4a mutation) functions through the enhancement of viral RNA synthesis. Furthermore, we show that WNV superinfection exclusion is reversible by the treatment of the replicon cells with a flavivirus inhibitor. The preestablished replication of the replicon could be suppressed by infecting the cells with the 2K mutant WNV but not with the wild-type virus. These results suggest that WNV superinfection exclusion is a result of competition for intracellular host factors that are required for viral RNA synthesis.
AuthorsGang Zou, Bo Zhang, Pei-Yin Lim, Zhiming Yuan, Kristen A Bernard, Pei-Yong Shi
JournalJournal of virology (J Virol) Vol. 83 Issue 22 Pg. 11765-76 (Nov 2009) ISSN: 1098-5514 [Electronic] United States
PMID19726510 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • RNA, Viral
Topics
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Cricetinae
  • Genes, Viral (physiology)
  • RNA, Viral (biosynthesis)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Superinfection (virology)
  • Vero Cells
  • Virus Attachment
  • Virus Replication (physiology)
  • West Nile virus (physiology)

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