Cross-reactivity between hepatitis C virus and influenza A virus determinant-specific cytotoxic T cells

The cellular immune response contributes to viral clearance as well as to l iver injury in acute and chronic hepatitis C virus (HCV) infection. An immu nodominant determinant frequently recognized by liver-infiltrating and circ ulating CD8(+) T cells of HCV-infected patients is the HCVNS3-1073 peptide CVNGVCWTV. Using a sensitive in vitro technique with HCV peptides and multi ple cytokines, we were able to expand cytotoxic T cells specific for this d eterminant not only from the blood of 11 of 20 HCV-infected patients (55%) but also from the blood of 9 of 15 HCV-negative blood donors (60%), while a second HCV NS3 determinant was recognized only by HCV-infected patients an d not by seronegative controls. The T-cell response of these healthy blood donors was mediated by memory T cells, which cross-reacted with a novel T-c ell determinant of the A/PR/8/34 influenza A virus (IV) that is endogenousl y processed from the neuraminidase (NA) protein. Both the HCV NS3 and the I V NA peptide displayed a high degree of sequence homology, bound to the HLA -A2 molecule with high affinity, and were recognized by cytotoxic T lymphoc ytes with similar affinity (10(-8) M). Using the HLA-A2-transgenic mouse mo del, we then demonstrated directly that HCV-specific T cells could be induc ed in vivo by IV infection. Splenocytes harvested from IV-infected mice at the peak of the primary response (day 7 effector cells) or following comple te recovery (day 21 memory cells) recognized the HCV NS3 peptide, lysed pep tide-pulsed target cells, and produced gamma interferon. These results exem plify that host responses to an infectious agent are influenced by cross-re active memory cells induced by past exposure to heterologous viruses, which could have important consequences for vaccine development.