Redox Regulation of the Influenza Hemagglutinin Maturation Process: A New Cell-Mediated Strategy for Anti-Influenza Therapy
Publication: Antioxidants & Redox Signaling
Volume 15, Issue Number 3
Abstract
Aim: 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). Results: 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. Innovation: 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. Conclusion: Redox-sensitive host-cell pathways exploited for viral replication are promising targets for effective anti-influenza strategies. Antioxid. Redox Signal. 15, 593–606.
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Published In
Antioxidants & Redox Signaling
Volume 15 • Issue Number 3 • August 1, 2011
Pages: 593 - 606
PubMed: 21366409
Copyright
Copyright 2011, Mary Ann Liebert, Inc.
History
Published in print: August 1, 2011
Published online: 5 July 2011
Published ahead of print: 19 May 2011
Published ahead of production: 2 March 2011
Accepted: 2 March 2011
Revision received: 25 February 2011
Received: 21 July 2010
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