| The emergence of HIV-1 strains resistant to antiviral drugs has made the need for an HIV/AIDS vaccine more compelling. Obstacles to the formulation of an effective HIV vaccine include the persistent nature of the infection, the antigenic variability of the virus, the mucosal route of entry, the immunosuppression associated with HIV infection, and the absence of defined correlates of protection. The principal focus of this thesis was to optimize vaccine strategies to elicit HIV-1 virus-specific cytotoxic T-lymphocyte (CTL) responses. BALB/c mice were immunized at mucosal sites with either the structural protein HIV-1 Env or V3 loop peptide antigen derived from HIV-1 Env, or the regulatory protein, HIV-1 Tat. In addition, the effectiveness of DNA immunization to elicit virus-specific CTL responses against Env or Tat was examined. Specific lysis of target cells by splenocytes from immunized BALB/c mice was determined using functional chromium-51 release assays. Each vaccine formulation was also assessed by its ability to induce antigen-specific cell-mediated and humoral responses with the more global view that all arms of the immune response should be induced to protect against a persistent infection, such as in the case of HIV, where the immune correlates of protection are not yet known.; The results presented in this thesis show that both mucosal and DNA immunization can be used to elicit HIV-1 virus-specific lysis of target cells. Mucosal immunization with these HIV-1 antigens also enhanced systemic and mucosal antibody responses above those observed with DNA vaccination alone. In many cases, immunization with DNA vaccine vectors encoding for various antigens has been found to elicit fairly efficient Type 1, or cell-mediated, immune responses but only weak or transient Type 2, or humoral, immune responses. Conversely, immunization with a protein antigen tends to elicit strong humoral immune responses, but only weak cellular immune responses are produced unless a specific adjuvant is used to modify that default immune response. The results from Env and Tat DNA prime/mucosal protein boost studies suggest that using a combination of these vaccine strategies could elicit the kind of prophylactic or therapeutic immune responses required for an effective HIV vaccine. |
