Grant: Project Grant

Despite the spectacular results for hepatitis C virus (HCV) clearance with new antiviral therapies, significant challenges remain for those with advanced liver fibrosis/cirrhosis. Progressive fibrosis results in symptomatic liver disease, predisposing to end-stage liver disease with a high mortality. Although antiviral therapy reduces the risk of liver cancer, cirrhotic patients remain at risk, and data suggests an atypically aggressive form can occur. Weakened responses to routine vaccinations and co-infections and chronicity with HCV re-exposure demonstrate the consequences of an immune system weakened by cirrhosis. Given that the majority of the 175 million HCV cases worldwide become chronic infections, with most remaining undiagnosed and only a fraction of known infections being treated annually, studies estimate the number of HCV+ individuals with cirrhosis will remain high for decades. An immune cell profoundly affected by chronic HCV infection is the CD8 T cell. Effective CD8 T cell responses are not only vital for viral clearance but are central to cancer surveillance and responses to other viral infections and increasingly important for vaccines in development against chronic viral infections requiring robust T cell immunity. We have found significant CD8 T cell dysfunction in cirrhotic HCV-infected individuals that persists long after cure, and suspect similar dysfunction in non-infectious liver disease. We are using gene sequencing methods to identify the underlying mechanism and are already following up on promising candidates. We are also using a mouse model emulating liver disease and CD8 T cell dysfunction, performing elegant mechanistic studies to complement our human research. These mice are clinically relevant with impaired responses to both cancer and immunotherapy, as is seen in humans. Our research will identify new immunorestorative therapeutic targets to improve clinical outcomes for cirrhotic HCV+ individuals and other liver diseases.