Suppression of a pro-apoptotic K⁺channel as a mechanism for hepatitis C virus persistence

Abstract

An estimated 3% of the global population are infected with hepatitis C virus (HCV), and the majority of these individuals will develop chronic liver disease. As with other chronic viruses, establishment of persistent infection requires that HCV-infected cells must be refractory to a range of pro-apoptotic stimuli. In response to oxidative stress, amplification of an outward K ϩ current mediated by the Kv2.1 channel, precedes the onset of apoptosis. We show here that in human hepatoma cells either infected with HCV or harboring an HCV subgenomic replicon, oxidative stress failed to initiate apoptosis via Kv2.1. The HCV NS5A protein mediated this effect by inhibiting oxidative stress-induced p38 MAPK phosphorylation of Kv2

Dengue Virus Capsid Protein Binding to Hepatic Lipid Droplets (LD) Is Potassium Ion Dependent and Is Mediated by LD Surface Proteins

“…p7 is an HCV viroporin that promotes membrane permeability to potassium and other cations (19), and although it seems essential for virus infection, its role in the viral life cycle is still partially unexplained (32,46). Additionally, HCV is also known to modulate the function of Kv2.1, a K ϩ -specific channel, through the action of the viral nonstructural protein NS5A (29). It is tempting to speculate that (i) the interaction of the HCV core protein with LDs is also K ϩ specific, being modulated at different stages of the viral life cycle by the viral proteins p7 and/or NS5A and (ii) equivalent DENV proteins influence intracellular potas- sium concentrations, therefore promoting the binding of the C protein to LDs and/or its release at a later stage of infection.…”

Viral dependence on cellular ion channels – an emerging anti-viral target?

“…Hepatitis C virus (HCV) chronically infects hepatocytes and, as such, has developed numerous mechanisms for maintaining the viability of infected host cells, primarily through the perturbation of numerous apoptotic stimuli, as reviewed in Giannini and Br echot [15]. One such mechanism involves the inhibition of a liverexpressed voltage-gated K + channel 2.1 (K v 2.1) by the HCV non-structural NS5A protein [16]. In hepatocytes, oxidative stress induces phosphorylation and activation of K v 2.1, which traffics to the plasma membrane and produces an outward K + current that triggers apoptotic induction [17].…”

Common Threads in Persistent Viral Infections

“…The antiapoptotic HCV protein NS3 has also been shown to target p53 and inhibit its function (22). An additional novel HCV antiapoptotic mechanism wherein the viral protein NS5A inhibits the Kv2.1 K ϩ channel, preventing hepatoma cells from apoptosis in response to oxidative stress, has recently been described (53).…”