Presentation of HCV antigens to naive CD8+T cells: Why the where, when, what and how are important for virus control and infection outcome

T cell-mediated protection against HCV depends on constantly activated effector CD8+T cells that control emergence, spread and expansion of the virus. Why these cells fail to contain HCV replication in 70–80% of the individuals who develop persistent viremia is not clear. Although many reviews have focused on HCV's ability to interfere with the process of antigen presentation by dendritic cells (DC), only few have discussed the mechanisms whereby HCV-derived antigens become available for presentation to naive CD8+T cells. The importance of these mechanisms has been recently brought to light by new insight into DC biology, antigen processing, HCV replication and the immune system's functional anatomy. This review explores the different immunological scenarios in which CD8+T cell responses against HCV may be initiated. It describes the critical factors limiting antigen sensing and capture by APC and antigen recognition by T cells, and discusses how these factors may favor chronicity of HCV infection. Despite the lack of critical detail and hard experimental proof, this review proposes a model whereby liver seclusion, unproductive infection of professional antigen presenting cells and lack of direct tissue damage hamper the launch of a virus-specific CD8+T cell response. The implications for vaccine development are also discussed.