Globally, hepatitis C virus (HCV) infects almost 200 million people and is a leading cause of cirrhosis and hepatocellular carcinoma – albeit several decades after initial infection. In a majority of cases, the virus is able to establish a persistent infection and, even with current gold standard treatments, sustained cure rates once the infection has become established are only around 50%. Researchers at the University of Leeds have now uncovered a previously unrecognized mechanism that allows the virus to evade the immune system and establish a chronic infection.
Establishment of persistent infection means that HCV-infected cells must be resistant to pro-apoptotic stimuli and the team found that one of the viral proteins, NS5A, is able to block apoptosis in human hepatoma cells either infected with HCV or harbouring an HCV subgenomic replicon. Amplification of an outward K+ current mediated by voltage-gated Kv2.1 channels normally precedes apoptosis triggered by oxidative stress and NS5A was found to block this process by inhibiting phosphorylation of Kv2.1 by p38 MAP kinase. Inhibition of a host cell ion channel by a viral protein as a means of preventing apoptosis has not previously been described, and the researchers hope that their findings could lead to new strategies for antiviral therapy. The study is published in the August 26th online edition of PNAS.