RECOMBINANT LISTERIA--BIOLOGIC VACCINE VECTOR FOR FIV

North Carolina State University Raleigh, Raleigh NC

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Abstract

Current data suggest a successful vaccine against the human immunodeficiency virus (HIV) must: l. induce an immune response at mucosal barriers, 2. induce a strong cytotoxic T-lymphocyte (CTL) response, and 3. induce an immune response that will be protective against multiple viral subgroups. Proposed here are studies to explore the use of recombinant Listeria monocytogenes as a biologic vaccine vector against lentivirus infections. The cell mediated immune response induced by Listeria monocytogenes infection is well characterized. L. monocytogenes infects macrophages, the central player in the immune response. After infection the bacterium enters the cytoplasm where it secretes antigens that are presented by the MHC I pathway for the induction of a cell-mediated immune response. L. monocytogenes infection of macrophages also leads to high levels of interleukin (IL) 12 and interferon (IFN)-gamma production (a type 1 cytokine profile). Listeria can be used to deliver lentiviral antigens into the cytoplasm of macrophages either through stable integration of viral sequences into the bacterial genome or by transfecting the bacteria with a plasmid containing viral genes that are driven by a eukaryotic promoter. The latter approach results in posttranslational modification of proteins while the first approach does not. Other key features of Listeria are that it's natural route of infection is through the gastro-intestinal mucosa and it can be attenuated to eliminate virulence even in immunocompromised individuals. The studies herein will: l. determine the viral gag genes that are most efficiently produced by recombinant L. monocytogenes in feline macrophages, 2. compare the immune response induced by FIV protein-expressing recombinant L. monocytogenes when administered by a parenteral or mucosal route and determine the efficacy of each route, 3. determine if FIVgag-expressing L. monocytogenes can deliver an envelope DNA vaccine plasmid that will be immunogenic. These studies will be performed using the feline immunodeficiency virus (FIV) infection of cats as a model for HIV infection of people. The value of the FIV model has been proven and will allow the comprehensive immunologic evaluation of a statistically significant number of animals in a highly controlled system. These studies will help determine whether it is rational to pursue the use of L. monocytogenes as a biologic vaccine vector against HIV in humans.