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In various human viral infections, the appearance of mutated epitopes displaying TCR antagonistic activity has been correlated with the severity and persistence of infection. In hepatitis C virus (HCV) infection, where the virus persistence has been associated with the rapid and substantial Ag modifications occurring during replication, TCR antagonism has been evidenced in CD8+ T cell responses. However, CD4+ T cell antagonism may be another important strategy by which HCV eludes a protective response, because sustained Th responses directed against several HCV Ags are associated with a self-limited course of infection. The data reported here represent the first evidence that variants of the hypervariable region (HVR1) of the putative Envelope 2 protein of HCV can act as powerful TCR antagonists for HVR1-specific CD4+ T cells isolated from HCV-infected individuals. Using classical antagonism assays …