Predicted substrate motifs for the lymphocyte specific protein tyrosine kinase Lck. Five tyrosines on a genotype 1b E2 sequence are predicted to be substrate sites (507, 594, 613, 697, 703). Analysis of 687 HCV E2 sequences representing all seven genotypes and 67 subtypes found that two of these tyrosines (507 and 613) are completely conserved suggesting positive selection (solid stars). CD4+ T cell lines expressing the full-length HCV E2 protein (384–747) and an E2 protein truncated to remove the C-terminal transmembrane domain (384–715) have been generated, and studies are underway to assess these proteins effects on T cell activation. The two conserved Lck substrate motifs are shown (CGPVYCFTP and PEATYSRCG). By alignments, the Y613 site aligns with the HPgV Y87 T cell inhibitory motif.