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AIM: To explore how to trigger an HLAI-restricted CD8+ T cell response to exogenously synthesized polypeptides in vivo.METHODS: Three mimetic therapeutic polypeptides based on the immunodominant CTL epitope of HBcAg, the B- epitope of HBV PreS2 region and a common T helper sequence of tetanus toxoid were designed and synthesized with Merrifield′s solid-phase peptide synthesis method. Their immunological properties of inducing TH1 polarization, CD8+HBV-specific CTL expansion and CD8+ T cell mediated cytotoxicity were investigated in HLA-A2 transgenic mice.RESULTS: Results demonstrated that the mimetic polypeptides comprised of the immunodominant CTL, B-,and T helper epitopes could trigger specifically and effectively vigorous CD8+ HBV-specific CTL-mediated cytotoxicity and TH1 polarization of T cells in HLA-A2 transgenic mice.CONCLUSION: A designed universal T helper plus Bepitopes with short and flexible linkers could dramatically improve the immunogenicity of CTL epitopes in vivo. And that the mimetic therapeutic peptides based on the reasonable match of the above CTL, B- and T helper epitopes could be a promising therapeutic peptide vaccine candidate against HBV infection.