Both T cell and B cell immune responses to HCV are being investigated. T cell studies are continuing in an effort to identify both cytotoxic T cell and helper T cell epitopes. We are studying the proliferative and CTL responses of patients with chronic HCV infections to peptide antigens and antigens expessed by recombinant DNA systems. Using predicted HLA A2 motifs from the HCV polyprotein, we identified five additional epitopes, 3 in the core protein, 1 in NS4B and 1 in NS5B. We found that HLA A2 patients with chronic HCV infections react to at least one of these epitopes in CTL assays but that 2 patients who had recovered from HCV did not react. We identified a new epitope in the NS3 protein to which patients with chronic HCV infections react. This epitope was also recognized only by patients who expressed HLA A2 even though the peptide did not contain a recognized A2 binding motif. Experimental genetic vaccines against HCV are being studied. BALB/c mice have been shown to develop antibody after injection with a plasmid that expresses HCV E2. We have extended these experiments to include the HCV core and E1 genes as well as E2. Inoculated mice exhibit both antibody and CTL responses to specific HCV antigens. Using human HLA A2 transgenic mice, we have investigated the ability of DNA vaccine to induce a human-like CTL responses. Mice were immunized with an HCV NS3 vaccine and were shown to develop CTL responses to the same epitopes recognized by A2 patients infected with HCV. in vitro correlates of immunity are being developed that will assist in evaluation of these plasmid based vaccines. Additional constructs are now being evaluated that include genes for cytosine expression as well as specific CTL epitopes from non-structural genes and non-specific helper epitopes. Prophylactic and therapeutic vaccines are under evaluation in Chimpanzees.
