T-cell responses are crucial for the control of viral infections, but the specific properties of antiviral T-cells required terminate viral replication and prevent establishment of chronic infections are poorly understood. Nearly 170 million people worldwide are infected with HCV, and those who develop chronic HCV infection are at risk for chronic hepatitis, cirrhosis, liver failure, and/or hepatocellular carcinoma. Few effective treatments from chronic HCV are available, and a preventative vaccine does not exist. However, not everyone who is infected with HCV develops persistent infection, and ~20% of persons acutely infected clear the virus within 6 months. Current evidence suggests that HCV-specific T cell responses are a key factor in the outcome of acute HCV infection. However, no clear immunological or virological differences have been identified which distinguish the T cell response in those who clear the virus from those who do not. Moreover the molecular mechanisms underlying the differences in immune responses in cleared versus chronic HCV infection are poorly defined. Better correlates of protective immunity are urgently needed to develop prophylactic vaccines and effective immunotherapies. In this application we propose to:
1. Identify gene expression signatures in HCV specific T cells early during acute HCV infection that are associated with early control of HCV infection versus progression to chronic infection;
2. Use cross-species comparison of gene expression profiles from HCV infection and cleared versus chronic viral infection in mice to identify candidate mechanisms that underlie the generation and differentiation of virus-specific T cells capable of rapid viral control;
3. Use chemical genomic screens in primary human T cells to identify novel modulators of memory differentiation.
The significance of this proposal lies in its potential to establish correlates of protective T-cell immunity against HCV by gene expression profiling and to identify agents capable of modulating T-cells towards more effective differentiation states. Importantly, the findings could be directly translated into clinical applications. Establishing a validated signature that corresponds to the immune response required to control a chronic infection will allow the accelerated development of prophylactic and therapeutic vaccines and immunotherapies.