TRANSCRIPTION-REGULATING VECTORS FOR ANTIVIRAL VACCINES

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Development of a vaccine against HIV-1 is critical to containing the spread of AIDS in both the United States and the world. Research suggests that an effective HIV vaccine must induce strong cellular immune responses, but many current HIV vaccine preparations do not induce such responses. The proposed studies evaluate a novel strategy for enhancing cellular immune responses to HIV-1 vaccines using "molecular adjuvants" that regulate the activity of dendritic cells (DCs) as they initiate primary immune responses. In contrast to previous molecular adjuvants that encode growth factors or cytokines, the Transcription-Regulating Vectors (TRV) examined here express signaling molecules that simultaneously regulate the expression of a variety of DC genes involved in antigen presentation and the induction of cellular immunity. These studies evaluate the fundamental hypothesis that molecular adjuvants encoding pleiotropic transcriptional regulators can provide a more powerful and flexible means of enhancing vaccine- induced immune responses than do either traditional exogenous adjuvants or previous molecular adjuvants. The proposed studies address the following specific aims: Aim 1: Optimize transcription regulating vectors (TRVs) to enhance dendritic cell induction of primary cellular immune responses. Aim 2: Evaluate costimulation of dendritic cell NF-kappaB and PKA/Sp 1 pathways as a means of enhancing primary and secondary cellular immune responses to an HIV-1 vaccine. Aim 3: Evaluate the efficacy of TRVs in eliciting antiviral cellular immune responses in vivo using a mouse DNA vaccine model. These studies will establish a basic research foundation to support the subsequent application of TRV technology to construction of safe and effective antiviral vaccines suitable for worldwide use in stemming the spread of HIV-1 infection.