[Source: Journal of Virology, full text: (LINK). Abstract, edited.]
Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection
Maria Joao Amorima,b, Richard Y. Kaoc and Paul Digarda,d
Author Affiliations: aDivision of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom bCell Biology of Viral Infection, Instituto Gulbenkian de Ciência, Oeiras, Portugal cDepartment of Microbiology and Research Center of Infection and Immunology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong dThe Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, United Kingdom
Novel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as “molecular staples” that stabilize interactions between NP monomers, promoting the formation of nonfunctional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early- and late-acting effects on the IAV life cycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of ribonucleoproteins (RNPs) that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP, and this work also provides proof of the principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.
Received 21 November 2012. Accepted 5 February 2013.
Address correspondence to Maria Joao Amorim, email@example.com.
Published ahead of print 13 February 2013
Supplemental material for this article may be found at http://dx.doi.org/10.1128/JVI.03123-12.
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