REGULATED FIV VECTORS FOR VACCINATION

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DESCRIPTION: (Adapted from Applicant's Abstract) Infection of cats with the feline immunodeficiency virus (FIV) produces an immunodeficiency syndrome with pathogenesis very similar to that observed in people infected with human immunodeficiency virus type 1 (HIV-1). FIV replicates primarily in CD4+ T cells and macrophages in vivo and produces progressive CD4+ T cell depletion that eventually renders the host susceptible to opportunistic infection. FIV also shares several genetic similarities with HIV and therefore provides an animal model for evaluating viral determinants of pathogenesis. The investigators have characterized FIV long terminal repeat (LTR) mutants and a vif-deletion mutant. The latter has been used as an attenuated virus that was capable of inducing protective immunity against infection with wild type FIV in vaccinated cats. For this proposal, the investigators hypothesize that molecular clones of FIV, attenuated for virulence, can be genetically engineered for regulated viral gene expression. Such FIV clones, physiologically regulated by administration of tetracycline (tet) to cats, will be tested as live-attenuated virus vaccines aimed at prevent infection with pathogenic challenge virus. This approach will make it feasible to examine the relationship of viral "threshold" level, protective immunity, and vaccine safety in cats inoculated with tet-regulated FIV clones. Most importantly, these experiments will test the usefulness of this approach of tet-regulated attenuated virus expression as a mechanism for increasing the safety of attenuated lentiviral vaccines. The investigators have also demonstrated that infection can be established in cats inoculated with plasmids containing the FIV provirus and that protective immunity against wild type FIV infection may be induced in cats inoculated with vif-deleted proviral DNA. Accordingly, "naked viral DNA" injection will be tested as a delivery system for infection of cats with tet-regulated attenuated FIV isolates.