TRANSCRIPTION-REGULATING VECTORS FOR ANTIVIRAL VACCINES

研制针对艾滋病毒-1的疫苗对于遏制艾滋病在美国和全世界的传播至关重要。研究表明，有效的艾滋病毒疫苗必须诱导强烈的细胞免疫反应，但目前许多艾滋病毒疫苗制剂不能诱导这种反应。拟议的研究评估了一种利用“分子佐剂”增强细胞对HIV-1疫苗免疫反应的新策略，这种“分子佐剂”在树突状细胞（dc）启动初级免疫反应时调节其活性。与之前编码生长因子或细胞因子的分子佐剂不同，这里研究的转录调节载体（TRV）表达信号分子，同时调节参与抗原呈递和细胞免疫诱导的多种DC基因的表达。这些研究评估了一个基本假设，即编码多效性转录调控因子的分子佐剂可以提供比传统外源性佐剂或以前的分子佐剂更强大、更灵活的手段来增强疫苗诱导的免疫反应。目标1：优化转录调节载体（TRVs）以增强树突状细胞诱导原代细胞免疫应答。目的2：评估树突状细胞NF-kappaB和PKA/Sp 1通路的共刺激作为增强对HIV-1疫苗的初级和次级细胞免疫反应的一种手段。目的3：利用小鼠DNA疫苗模型评估TRVs在体内引发抗病毒细胞免疫反应的功效。这些研究将建立一个基础研究基础，以支持随后将TRV技术应用于构建安全有效的抗病毒疫苗，适合在世界范围内使用，以遏制艾滋病毒-1感染的传播。

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.