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Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy

2011; Mary Ann Liebert, Inc.; Volume: 15; Issue: 3 Linguagem: Inglês

10.1089/ars.2010.3512

1557-7716

Rossella Sgarbanti, Lucia Nencioni, Donatella Amatore, Paolo Coluccio, Alessandra Fraternale, Patrizio Sale, Caterina Loredana Mammola, Guido Carpino, Eugenio Gaudio, Mauro Magnani, Maria Rosa Ciriolo, Enrico Garaci, Anna Teresa Palamara,

Neuroscience of respiration and sleep

The aim of this study was to determine whether GSH-C4, a hydrophobic glutathione derivative, affects in vitro and in vivo influenza virus infection by interfering with redox-sensitive intracellular pathways involved in the maturation of viral hemagglutinin (HA).GSH-C4 strongly inhibited influenza A virus replication in cultured cells and in lethally infected mice, where it also reduced lung damage and mortality. In cell-culture studies, GSH-C4 arrested viral HA folding; the disulfide-rich glycoprotein remained in the endoplasmic reticulum as a reduced monomer instead of undergoing oligomerization and cell plasma-membrane insertion. HA maturation depends on the host-cell oxidoreductase, protein disulfide isomerase (PDI), whose activity in infected cells is probably facilitated by virus-induced glutathione depletion. By correcting this deficit, GSH-C4 increased levels of reduced PDI and inhibited essential disulfide bond formation in HA. Host-cell glycoprotein expression in uninfected cells was unaffected by glutathione, which thus appears to act exclusively on glutathione-depleted cells.All currently approved anti-influenza drugs target essential viral structures, and their efficacy is limited by toxicity and by the almost inevitable selection of drug-resistant viral mutants. GSH-C4 inhibits influenza virus replication by modulating redox-sensitive pathways in infected cells, without producing toxicity in uninfected cells or animals. Novel anti-influenza drugs that target intracellular pathways essential for viral replication ("cell-based approach") offer two important potential advantages: they are more difficult for the virus to adapt to and their efficacy should not be dependent on virus type, strain, or antigenic properties.Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies.