| The vaccinia virus TianTan (VTT) has been modified as an HIV vaccine vector in China and has shown excellent performance in immunogenicity and safety. However, its adverse effects in immunosuppressed individuals warrant the search for a safer vector in the following clinic trails. In this study, we deleted the C7L and K1L genes of VTT or replaced C8L-K3L genes with HIV gag gene and GFP gene. Then we constructed seven recombinant vaccinia strains?(?), VTTAK1L, VTT?C7LK1L VTKgpe?C7L, VTKgpe?K1L, VTT?C7LK1L-gag and VTT ? C8-K3-gag. The pathogenicity and immunogenicity of these recombinants were evaluated in mouse and rabbit models. Comparing to parental VTT and VTKgpe, VTTAC7L, VTT?K1L and VTKgpeAC7L, VTKgpeAK1L showed significantly decreased replication capability in CEF, Vero, BHK-21 and HeLa cell lines. In particular, replication of?VTO7LK1L VTT?C7LK1L-gag and VTT?C8-K3-gag decreased more than 10-fold in all four cell lines. The virulence of all these mutants were decreased in BALB/c mouse and rabbit models; VTTAC7LK1L, VTTAC7LK1L-gag and VTT?C8-K3-gag once again showed the greatest attenuation, having resulted in no evident damage in mice and erythema of only 0.4-0.5 cm diameter in rabbits, compared to 1.48 cm for VTT.In four strategies, VTKgpeAC7L, VTKgpe?K1L, VTTAC7LK1L-gag and VTT? C8-K3-gag elicited as strong cellular and humoral responses against HIV genes as did VTKgpe, while cellular and humoral immune response against the vaccinia itself was reduced, especially when these recombinant viruses were immunized twice. In Mice, T-cell immunogenicity against HIV could be enhanced by DNA prime and recombinant virus boost vaccination. These data show that deletion of C7L and K1L genes leads to significantly decreased virulence without compromising animal host immunogenicity, and may thus be key to creating a more safe and effective HIV vaccine vector. And more effective strategy will be studied in the future. |
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