Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity.
In recent years, increasing levels of resistance to the four FDA-approved anti-influenza virus drugs have been described and vaccine manufacturers have experienced demands that exceed their capacity. This situation underlines the urgent need for novel antivirals as well as innovations in vaccine production in preparation for the next influenza epidemic. Here we report the development of a cell-based high-throughput screen which we have used for the identification of compounds that modulate influenza virus growth either negatively or positively. We screened a library of compounds with known biological activity and identified distinct groups of inhibitors and enhancers that target sodium channels or protein kinase C (PKC). We confirmed these results in viral growth assays and find that treatment with a sodium channel opener or PKC inhibitor significantly reduces viral replication. In contrast, inhibition of sodium channels or activation of PKC leads to enhanced virus production in tissue culture. These diametrically opposing effects strongly support a role for PKC activity and the regulation of Na(+) currents in influenza virus replication and both may serve as targets for antiviral drugs. Furthermore, we raise the possibility that compounds that result in increased viral titers may be beneficial for boosting the production of tissue culture-grown influenza vaccines.
Hoffmann
H-Heinrich
HH
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Palese
Peter
P
Shaw
Megan L
ML
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D009975:Orthomyxoviridae / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D020536:Enzyme Activators; D047428:Protein Kinase Inhibitors; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D011493:Protein Kinase C