This study analyzed the T lymphocyte response during and after acute resolving HCV infection in three individuals using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute HCV infection was associated with a broad T helper and cytotoxic T lymphocyte (CTL) response that persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive individuals, CTL responses were more common in those who had cleared viremia compared to those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found during and after acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection. The study also examined the breadth of the HCV-specific CD8⁺ lymphocyte response in a subject with resolving acute HCV infection. A 42-year-old intravenous drug user presented with acute HCV infection, characterized by elevated ALT and HCV RNA positivity. ALT subsequently normalized, and HCV RNA became negative. Blood samples were available from this subject during and after acute illness, allowing for the detailed study of HCV-specific T cell responses. The study identified eight different epitopes targeted simultaneously in this subject, which were presented by three different class I alleles. The breadth of the response was greater than that typically observed in chronic infection. The study also analyzed the persistence and fluctuation in CTL responses after acute disease. The study found that the populations of CTLs with different antigenic specificities fluctuated at a time when plasma viremia had been cleared below the detection limit in blood and there was no further evidence of biochemical hepatitis. These expansions of antiviral CTLs months after infection may be caused by bystander activation by other immunogens or may represent continued presentation of HCV antigens to CTLs in lymphoid organs or the liver. The study also found that the phenotype of CTLs in this phase after acute infection was of interest, as these populations of tetramer-positive cells did not show an activated phenotype, which could explain why no concomitant rise in ALT was observed. Low expression of CD38 and HLA class II on antiviral cells is similarly found in patients who have successfully cleared hepatitis B virus or controlled acute EBV infection.This study analyzed the T lymphocyte response during and after acute resolving HCV infection in three individuals using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute HCV infection was associated with a broad T helper and cytotoxic T lymphocyte (CTL) response that persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive individuals, CTL responses were more common in those who had cleared viremia compared to those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found during and after acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection. The study also examined the breadth of the HCV-specific CD8⁺ lymphocyte response in a subject with resolving acute HCV infection. A 42-year-old intravenous drug user presented with acute HCV infection, characterized by elevated ALT and HCV RNA positivity. ALT subsequently normalized, and HCV RNA became negative. Blood samples were available from this subject during and after acute illness, allowing for the detailed study of HCV-specific T cell responses. The study identified eight different epitopes targeted simultaneously in this subject, which were presented by three different class I alleles. The breadth of the response was greater than that typically observed in chronic infection. The study also analyzed the persistence and fluctuation in CTL responses after acute disease. The study found that the populations of CTLs with different antigenic specificities fluctuated at a time when plasma viremia had been cleared below the detection limit in blood and there was no further evidence of biochemical hepatitis. These expansions of antiviral CTLs months after infection may be caused by bystander activation by other immunogens or may represent continued presentation of HCV antigens to CTLs in lymphoid organs or the liver. The study also found that the phenotype of CTLs in this phase after acute infection was of interest, as these populations of tetramer-positive cells did not show an activated phenotype, which could explain why no concomitant rise in ALT was observed. Low expression of CD38 and HLA class II on antiviral cells is similarly found in patients who have successfully cleared hepatitis B virus or controlled acute EBV infection.