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T cell immunity to hepatitis C virus: Lessons for a prophylactic vaccine. There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.