Development of dendritic cell-based vaccines for the treatment of HIV-infected patients.
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Cobb, Amanda J., 1979-
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Dendritic cells (DCs) are professional antigen-presenting cells of the immune system with the ability to induce and control T and B cells responses. Monocytes have been used as precursors to generate DC vaccines ex vivo. Monocyte-derived DCs have been used as vaccines in clinical trials to treat cancer and infectious disease by eliciting potent T cell responses. Infection with Human Immunodeficiency Virus (HIV) almost invariably leads to a chronic disease. Eventually the destruction of the immune system culminates into Acquired Immune Deficiency Syndrome (AIDS). Since the advent of Highly Active Antiretroviral Therapy (HAART), HIV patients have been able to control viral levels. However, with prolonged use of treatment, these patients experience serious adverse effects such as liver and mitochondrial toxicity that can potentially become fatal. Long-Term Non-Progressors (LTNP) are a unique subpopulation of HIV patients that are able to control their viral load without HAART. Studies revealed HIV-specific polyfunctional CD8⁺ T cells to be vital for viral control. Thus, we have focused our efforts on devising therapeutic HIV DC vaccines to increase the quality of CD8⁺ T cell responses in chronic HIV infected patients. First, we conducted a series of preclinical development assays of GM-CSF/IFN-α and GM-CSF/IL-15 HIV DC vaccines loaded with a mixture of HIV-1-antigen lipopeptides (ANRS HIV-LIPO-5 vaccine), which is comprised of five HIV-1-antigen peptides (Gag₁₇₋₃₅, Gag₂₅₃₋₂₈₄, Nef₆₆₋₉₇, Nef₁₁₆₋₁₄₅, and Pol₃₂₅₋₃₅₅) each covalently linked to a palmitoyl-lysylamide moiety, and activated with LPS. Functional assays demonstrated that the DC vaccines expressed DC differentiation markers and displayed typical morphology which included the presence of dendrites important for cellular interaction. Potency assays proved the DC vaccines were capable of eliciting HIV-1-antigen-specific CD4⁺ and CD8⁺ T cell responses. Our studies have demonstrated the use of DC vaccines in eliciting HIV-specific CD8⁺ T cells responses in vitro. Furthermore, the pre-clinical development of the GM-CSF/IFN-α DC vaccine activated with LPS led to the evaluation of safety and immunogenicity in a Phase I/II clinical trial in chronically HIV-1-infected patients on HAART (clinicaltrials.gov identifier: NCT00796770).