Induction of cytotoxic T lymphocyte responses against hepatitis delta virus antigens which protect against tumor formation in mice

The cellular immune response is a crucial defense mechanism against hepatot ropic viruses and in chronic viral hepatitis prevention. Moreover, hepatiti s delta virus (HDV) immunogenicity may be an important component in the dev elopment of prophylactic and therapeutic vaccines. Therefore, we evaluated the inuntmogenicity of the small (HDAg) or large delta antigen (LHDAg) to b e used as a DNA-based vaccine. We immunized different mouse haplotypes, det ermined cellular immune responses, and tested protection of animals against tumor formation using syngeneic tumor cells stably expressing the delta an tigens. Both LHDAg and HDAg primed CD4+ and CD8+ T cell immunity against bo th forms of delta antigens. CD8+ T cell frequencies were about 1% and antig en-specific CD8+ T cells remained detectable directly ex vivo for at least 35 days post-injection. No anti-delta antibody responses could be detected despite multiple detection systems and varied immunization approaches. We o bserved protection against syngeneic tumor formation and growth in mice imm unized with DNA plasmids encoding secreted or intracellular forms of HDAg a nd LHDAg but not with recombinant HDAg establishing the generation of signi ficant cellular immunity in vivo. Both CD4+ and CD8+ T cells were required for antitumoral activity as determined by in vivo T cell depletion experime nts. The results indicate that DNA-based immunization with genes encoding L HDAg and HDAg induces strong T cell responses and, therefore, is an attract ive approach for the construction of therapeutic and prophylactic T cell va ccines against HDV. (C) 2001 Elsevier Science Ltd. All rights reserved.