The aim of this application is to test the suitability of El-deleted adenoviral recombinants to serve as vaccine carriers for mucosal immunization to HIV-1. Such recombinants induce potent central T and B cell mediated immune responses to the transgene product upon systemic inoculation or upon application to mucosal surfaces. They also induce immunity at distant mucosal sites, including the genital tract, especially after application to the airways. The magnitude of the mucosal immune response can be augmented by using prime-boost regimens. In order to test if El-deleted adenoviral recombinants are suitable to induce genital immunity to HIV-1, the applicants propose in the first aim to construct El-deleted adenoviral recombinants and plasmid vectors expressing either the gpl20 of the HIV(IIIB) or of the HIV (89.6P) strain. Upon in vitro analysis, the adenoviral construct expressing gpl20 of the HIV(IIIB) strain will be tested in mice for induction of mucosal B and T cell responses to HIV-1. Prime-boost experiments using the adenoviral recombinant, either alone or in combination with a DNA vaccine expressing the same antigen, will be conducted to enhance and prolong the genital immune response. Provided these studies show induction of good immunity to HIV-1 in the mouse model, the applicant will then in the 3rd aim, in collaboration with Dr. N. Letvin, conduct a limited trial in rhesus monkeys using the adenoviral recombinant expressing the gpl20 of HIV(89.6P) virus for which a challenge model is available. In the 4th aim the applicant will attempt, using the mouse model, to enhance the magnitude and duration of the mucosal immune response to HIV- 1 by using genetic adjuvants, i.e., plasmid vectors expressing mouse cytokines, for priming with the DNA vaccine followed by an i.n. booster immunization with the adenoviral recombinant. Again, these studies will be conducted with constructs expressing gpl20 of the HIV(IIIB) strain.
