Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity

Hepatitis C Virus (HCV) is a major public health concern, with no effective vaccines currently available and 3% of the world's population being infected. Despite the existence of both B- and T-cell immunity in HCV-infected patients, chronic viral infection and HCV-related malignancies progress. Here we report the identification of a novel HCV TCR from an HLA-A2-restricted, HCV NS3:1073–1081-reactive CTL clone isolated from a patient with chronic HCV infection. We characterized this HCV TCR by expressing it in human T cells and analyzed the function of the resulting HCV TCR-transduced cells. Our results indicate that both the HCV TCR-transduced CD4+ and CD8+ T cells recognized the HCV NS3:1073–1081 peptide-loaded targets and HCV+ hepatocellular carcinoma cells (HCC) in a polyfunctional manner with cytokine (IFN-γ, IL-2, and TNF-α) production as well as cytotoxicity. Tumor cell recognition by HCV TCR transduced CD8− Jurkat cells and CD4+ PBL-derived T cells indicated this TCR was CD8-independent, a property consistent with other high affinity TCRs. HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections.
Author Summary Hepatitis C Virus (HCV) is a major public health concern with a large number of individuals infected (3% world wide). Currently, there is no effective vaccine available to prevent HCV infection and the treatment is effective in less than half of all patients. Therefore, many patients have long term infections that lead to severe liver damage or liver cancer. It has been shown that some HCV infected patients can eliminate the virus and the host immune system is involved. The problem is most people do not have the capacity to fight their HCV infection. We have developed a gene therapy based approach where a patient's own immune cells can be made to recognize cells expressing HCV genes. This can be accomplished regardless of his or her natural capacity to fight their HCV infection. This manuscript describes how normal immune cells can be genetically altered to recognize cells expressing HCV proteins and characterizes their reactivity and sensitivity to antigen stimulation.