DNA-Mediated Immunization in Mice Induces a Potent MHC Class I-Restricted Cytotoxic T Lymphocyte Response to the Hepatitis B Envelope Protein

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Abstract
The particulate form of the major envelope or surface (S) protein of hepatitis B virus (HBV) can be taken up by antigen-presenting cells and processed for class I presentation as an exogenous protein. We have used several DNA plasmid vectors expressing the HBV envelope proteins to determine whether these sequences are able to induce cytotoxic T lymphocyte (CTL) responses in BALB/c mice after intramuscular DNA injection. A potent and specific induction was obtained, which can be detected ex vivo using either specific or nonspecific (interleukin-2) stimulation in cell culture, and the DNA-primed CTL responses are stronger than those obtained with protein injection with either stimulation protocol. The CTL response induced by DNA-based immunization is both canonical and highly specific as indicated by the nature of the epitope presented (amino acids 28–39), the class I allele used (Ld), and the T lymphocytes involved (CD8+). The CTL response is initiated between 3 and 6 days after DNA injection. By 6–12 days after a single DNA injection, ex vivo cytolytic activity is nearly maximal, and similar high levels of activity can still be detected 4 months after injection. The possibility is discussed that the unusual mode of delivery of the antigen to the immune system provided by in situ expression might allow HBV envelope antigen to be taken up and processed for class I presentation as an exogenous protein in addition to activating potentially the classical endogenous pathway. Direct gene transfer allows in situ protein synthesis for the purpose of inducing an immune response. One of the most remarkable features of this DNA-mediated immunization procedure is that expression of small amounts of proteins gives rise to strong and broad-based immune responses. Here, Davis et al. use several DNA plasmid vectors expressing the hepatitis B virus envelope proteins to determine whether these sequences are able to induce cytotoxic responses in mice after intramuscular DNA injection. A potent and specific induction is obtained that is both canonical and highly specific, as indicated by the nature of the epitope presented, the class I allele used, and the T lymphocytes involved (CD8+). The possiblity is discussed that uptake and processing of exogenous protein may contribute to the response. One possible clinical application of DNA vaccines is their use as a therapeutic tool for treatment of hepatitis B virus carriers.