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196 Induction of HIV-Specific Immune Responses by Targeted Delivery of Antigens to Dendritic/Antigen-Presenting Cells in Vivo
B. P. Nayak2, S. Husain2, S. Gangadhara2, and A. M. Jabbar*1
1Emory Vaccine Ctr. at Yerkes and 2Emory Univ. Sch. of Med., Atlanta, GA, USA
Background: Dendritic cells (DCs) serve as sentinels of the immune system and are the potent activators of primary T-cell responses. DCs have the ability to capture antigens in the periphery, process them in their intracellular compartments and move to the T-cell areas of secondary lymphoid organs for presentation to elicit robust immune responses. During this process of maturation, DCs express a number of costimulatory molecules (CD40, B7) that are critical in the amplification of intracellular signals in the T-cell activation process.
Methods: We focused on a few of the well-characterized T-cell proteins (CD40L and CTLA4) and covalently linked them to HIV-189.6P envelope glycoproteins. The genes encoding the extracellular domains of these transmembrane proteins were constructed in DNA vaccine vectors and tested for the expression of appropriate fusion proteins using a transfection system in vitro.
Results: Our expression analyses demonstrated that the chimeric genes produced proteins (Env89.6P:CD40L and CTLA4:Env89.6P) of the expected molecular mass and had the ability to bind to cognate receptors on the surface of antigen-presenting cells (APCs). We tested these chimeric genes as DNA vaccines for their ability to induce both humoral (Ab) and cellular (CD8+) immune responses in mice. When compared with HIV-env (gp120), the genetically modified gp120 proteins exhibited enhanced levels of env-specific Ab and CD8+ T-cell responses in this animal model system.
Conclusions: These results strongly suggest that the costimulatory innate immune mechanisms have the potential to augment antigen-specific immune responses induced by DNA vaccines.
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