Worldwide an estimated 170 million people are chronically infected with the hepatitis C virus (HCV) and, after decades, have a significant risk at developing severe liver disease and liver cancer. Until recently therapy was accompanied with severe side effects and efficacies ranged from 50 to 70%. Recently HCV-specific direct antiviral agents increased efficacy rates to above 95% for most infected individuals. However, these therapies are hugely expensive and certain difficult-to-treat patient populations remain. We have firm data that B-lymphocytes are carriers of infectious virus. When we injected purified Bcells from chronically infected patients into mice with a humanized liver, infection was established. On the other hand, when we injected serum from the same patient no infection was observed, most likely due to the presence of neutralizing antibodies. Using B-cells and serum from an acute patient resulted in the inversed result. In the latter case no neutralizing antibodies were present in the serum and the B-cells did not seem to have the capacity to transfer the virus. Interestingly HCV infection is associated B-cell lymphoproliferative disorders, suggesting an intimate interaction between B-cells and the virus. In this project we will perform a detailed characterization of the B-cell (sub)population that is infected. In addition we will evaluate whether B-cell infection has an impact on the evolution of acute infection and whether is plays a role in therapy outcome.