Hepatitis C virus (HCV) is a global health issue, with infection progressing to chronic disease in the majority of cases and subsequently leading to an increased risk of liver cirrhosis and cancer. Several direct-acting antiviral agents exist, which target proteins produced by the virus that are essential to its life cycle. However, mutations in these viral proteins can produce resistance to antiviral agents, thereby reducing their efficiency and presenting a barrier to effective treatment. A number of such mutations have been identified in the HCV protein NS5A. As such, a thorough understanding of the mechanism of this viral protein within liver cells is essential to developing strategies to overcome resistance.
Working in collaboration with colleagues at Oxford, the Goethe University, and the University of Leeds, Artem Smirnov from the Lu lab discovered that ASPP2, a key regulator of the tumour suppressor protein p53, binds to the NS5A protein of HCV. Smirnov and colleagues characterised this binding, identifying the precise regions involved: the SH3 domain of ASPP2 and PxφPx+ motif of NS5A. Using a variety of biochemical techniques, they showed that ASPP2 positively influences HCV replication and may also facilitate HCV transmission from infected cells to neighbouring cells.
This work gives new insights into how HCV interacts with its host and adds to our growing fundamental understanding of HCV biology; an essential resource for addressing clinical challenges linked to HCV.