An effective way to generate human CD4+ and CD8+ T cell responses is by presenting antigens on dendritic dells (DCs), a system of antigen presenting cells (APCs) that stimulate innate and adaptive immune responses. Immunization strategies that utilize or target human DCs to enhance immunity in chronic HIV infection have shown promise in previous studies, but further research is required to optimize DC vaccine candidates. Ideally, a DC-targeting vaccine vector should deliver relevant HIV antigens for presentation, while concurrently activating DCs to upregulate surface costimulatory molecules and produce pro Th1 cytokines in order to to prime HIV-specific polyfunctional CD4+ and CD8+ T cell responses. Recombinant killed but metabolically active Listeria Monocytogenes vectors may fulfill these criteria, while offering potential advantages in terms of both immunogenicity and safety when compared with various attenuated viral and bacterial vectors. In the proposed research, the use of a recombinant killed but metabolically active Listeria Monocytogenes expressing HIV-1 gag (KBMA Lm-gag) will be investigated as an antigen loading and activation/maturation platform for DCs to evaluate its potential use in DC vaccine formulations for chronic HIV infection.
The specific aims are to: (1) assess activation/maturation and efficiency of antigen presentation of DCs derived from HIV seropositive donors following infection with KBMA Lm-gag;(2) evaluate the ability of KBMA Lm-gag infected DCs derived from HIV seropositive patients to prime naive T cells to form polyfunctional HIV-1 gag-specific CD4+ and CD8+ T cells that possess high functional avidity; and (3) investigate whether pre-existing immunity to Lm impacts responses elicited by KBMA lm-gag infected DCs in terms of immunogenicity, immune activation, and susceptibility of CD4+ T cells to HIV infection. These studies will help determine whether KBMA Lm-gag may serve as an exciting new vector for HIV immunotherapy that utilizes or targets DCs to facilitate control of HIV infection.
The field of HIV vaccinology has recently suffered set-backs, inspiring the investigation of novel modes of antigen delivery in order to stimulate HIV-specific immunity. In order to move forward from this point, we have applied aspects of the knowledge gained from failed attempts to the design and evaluation of the construct utilized in the proposed study.
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