Hypervariable region 1 variants act as TCR antagonists for hepatitis C virus-specific CD4(+) T cells

In various human viral infections, the appearance of mutated epitopes displ aying TCR antagonistic activity has been correlated with the severity and p ersistence of infection. In hepatitis C virus (HCV) infection, where the vi rus persistence has been associated with the rapid and substantial Ag modif ications 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 susta ined Th responses directed against several HCV Ags are associated with a se lf-limited course of infection. The data reported here represent the first evidence that variants of the hypervariable region (HVR1) of the putative E nvelope 2 protein of HCV can act as powerful TCR antagonists for HVR1-speci fic CD4(+) T cells isolated from HCV-infected individuals. Using classical antagonism assays, we observed strong inhibition of cellular proliferation and cytokine production when the agonist and the antagonist ligands were si multaneously presented by the same APCs, The presence in HVR1 of conserved residues, critical for binding to KLA-DR molecules, supports the function o f HVR1 variants as TCR antagonists. In conclusion, our data evidence an ant agonism phenomenon, which was achieved by naturally occurring class II-rest ricted T cell epitopes whose mechanism was addressed in terms of the antago nist capacity to inhibit agonist-mediated TCR down-regulation and early sig nal transduction.