Lethality in mice infected with recombinant vaccinia virus expressing hepatitis C virus core protein

<正> OBJECTIVE: To establish a mouse model of HCV core expression and investigate the toxicity of HCVcore protein or the possible pathogenic effects.METHODS: A series of vaccinia viral expression vectors were engineered to express 5' portion of HCVgenes including 5' non-translated region (NTR), core protein, and portion of the E1 gene. These HCVsequences were fused to a luciferase reporter gene and inserted into a vaccinia virus expression vector(pSC11) adjacent to the vaccinia virus promoter, p7.5. The recombinant DNA constructs were packedinto infectious recombinant chimeric viruses. The expression of HCV core protein was examined incultured cells after infection with these viruses. Death of the infected mice was investigated by specificcorrelation to the expression of HCV core protein and its expression levels.RESULTS: The recombinant virus (VNCE-LUA) expressed HCV core protein and anenvelope-luciferase fusion protein in cultured cells. When Balb/c mice were inoculated intraperitoneallywith more than 10～7 pfu per mouse of VNCE-LUA, death occurred immediately. The mortality wasdependent on the amount of VNCE-LUA virus inoculated. All mice inoculated with 3×10～8 pfu ofVNCE-LUA died within 4 days of infection and 50% of mice inoculated with 3×10～7 pfu of VNCE-LUAdied within 7 days of infection. No death occurred in mice inoculated with 3×10～8 pfu of a controlrecombinant vaccinia virus, which expressed luciferase but not the HCV core and envelope proteins.Deletion of core sequences from VNCE-LUA rapidly reduced the mortality of infected mice whereasdeletion of envelope sequence did not. SCID mice infected with VNCE-LUA died 2-3 days afterinfection, suggesting that the HCV-core induced mortality is not dependent on host T-or B-cell responsesto core protein.CONCLUSIONS: HCV core protein can be lethal to mice when expressed in vivo and this specificlethality is independent of T-cells or B-cells. The findings and model itself provide a useful tool for furtherinvestigation on potential pathological effects as well as the potential toxicity of the HCV core protein.