Abstract
Alphaviruses are arthropod-borne viruses that can cause fever, rash, arthralgias, and encephalitis. The mosquito species Aedes aegypti and Aedes albopictus are the most frequent transmitters of alphaviruses. There are no effective vaccines or specific antivirals available for the treatment of alphavirus-related infections. Interestingly, changes in ion concentration in host cells have been characterized as critical regulators of the alphavirus life cycle, including fusion with the host cell, glycoprotein trafficking, genome translation, and viral budding. Cardiac glycosides, which are classical inhibitors of the Na+ K+ ATPase (NKA), can inhibit alphavirus replication although their mechanisms of action are poorly understood. Nonetheless, results from multiple studies suggest that inhibition of NKA may be a suitable strategy for the development of alphavirus-specific antiviral treatments. This review is aimed at exploring the role of changes in ion concentration during alphavirus replication and at considering the possibility of NKA as a potential therapeutic target for antiviral drugs.
Highlights
Viruses of the genus Alphavirus genus are a subset of the family Togaviridae [1]
We suggest two possible hypotheses: first, cardiac glycosides have a clear impact on intracellular ion concentrations, and second, they trigger intracellular signaling cascades that can impair virus replication
Some data suggest that Src activation by cardiac glycosides can trigger MAPK (extracellular signal-regulated kinase (ERK) 1/2) signaling through the Raf-MEK cascade, resulting in the inhibition of viral gene expression; these data were generated in HIV-infected cells treated with a cardiotonic steroid [84]
Summary
Viruses of the genus Alphavirus genus are a subset of the family Togaviridae [1]. Among the 31 virus species that are included in this family [2], only salmon pancreatic disease virus and Southern elephant seal virus are not arthropod-borne [3]. They are used in the treatment of patients with heart failure because of their potent inotropic effect [33, 34] Cardiac glycosides, such as ouabain and digoxin, disrupt the flow of the Na+ and K+ ions, resulting in a significant change in the cellular ion gradient. Alphavirus infection is initiated by binding to the surface cell host receptor [44] which results in fusion and internalization [45]; an alternate pathway for cell penetration includes direct transfer of virus RNA through pores formed in the plasma membrane during infection [46,47,48]. An alternate mechanism for nucleocapsid disassembly involves pore formation by the virus E1 protein which serves to direct protons into the viral particle, thereby facilitating the uncoating viral RNA [55] via the actions of ion channels that promote Na+/Cl+ and Na+/K+ exchange by the viral protein 6 k [56]
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