Stimulation of DNA vaccines by IRF

描述（由申请人提供）：这些研究的长期目的是确定干扰素调节因子家族（IRF）转录因子在免疫应答中的作用。本文的应用重点在于阐明IRF增强DNA免疫应答的分子机制。在过去的几年中，我们已经确定并表征了三种新的irf: IRF-3， IRF-5和IRF-7。这些IRF作为病毒诱导信号的直接转导体，在早期炎症基因的诱导中发挥关键作用。然而，它们的功能超出了先天免疫，我们已经确定IRF-7是巨噬细胞分化因子。此外，IRF-1、IRF-3或IRF-7的表达增强了DNA引起的免疫反应。在本研究中，我们希望研究IRF对两种病毒抗原（流感病毒血凝素蛋白和HIV-1包膜蛋白）介导的DNA免疫应答的辅助作用的分子基础。为此，这项研究有三个目标，我们将提出以下问题：IRF对两种不同抗原免疫应答的佐剂作用相同吗？我们将分析肱骨和细胞对HIV-1的gp 160的反应，并将其与对流感HA的反应进行比较。目标# 2。IRF的辅助作用是否由I型IFN介导？IRF被证明可以刺激I型IFN的诱导，因此我们将在缺乏I型IFN受体的小鼠中检查IRF的辅助作用。IFNa的共表达对DNA免疫反应的影响将被检测以进行比较。目标# 3。在佐剂效果中是否需要IRF激活？我们将检验本构活性IRF-3和！RF-7在DNA中介导免疫反应。意义：与传统疫苗相比，DNA介导的疫苗接种提供了有效的病毒特异性CD4+和CD8+反应，这对于控制包括HIV-1在内的许多病毒感染的病毒血症至关重要，并且其分布将是容易和经济的。因此，开发DNA诱导免疫应答的强效佐剂具有重要的流行病学和经济意义。

DESCRIPTION (provided by applicant): The long term of these studies is to determine the role of transcription factors of the interferon regulatory factor family (IRF) in immune responses. This application is focused on the clarification of molecular mechanism by which IRF enhance the DNA raised immune response. Over the past years we have identified and characterized three novel IRFs: IRF-3, IRF-5 and IRF-7. These IRF functions as direct transducers of virus induced signaling and play a critical role in induction of the early inflammatory genes. However, their function extends beyond innate immunity and we have identify IRF-7 as a macrophage differentiation factor. Furthermore the expression of IRF-1, IRF-3 or IRF-7 enhances a DNA raised immune response. In the proposed study we wish to examine the molecular basis of the adjuvant effect of IRF on DNA mediated immune response by two viral antigens, hemaglutinin protein of influenza virus and envelope protein of HIV-1. To this effect the study has three Aims in which we shall ask following questions: Aim#1. Is the adjuvant effect of IRF on immune response to two distinct antigens identical? We shall analyzed humeral and cellular response to gp 160 of HIV-1 and compare it with the response to HA of influenza. Aim #2. Is the adjuvant effect of IRF mediated by Type I IFN? The IRF were shown to stimulate induction of Type I IFN we shall therefore examine the adjuvant effect of IRF in mice that is lacking the Type I IFN receptor. Effect of co-expression of IFNa on DNA raised immune response will be examined for comparison. Aim #3. Is there a requirement for IRF activation in the adjuvant effect? We shall examine the adjuvant effect of constitutively active IRF-3 and !RF-7 on a profile of DNA mediate immune responses. Significance: Compared to the conventional vaccines, the DNA mediated vaccination provides elicits potent virus specific CD4+ and CD8+ responses that are critical for controlling viremia in many viral infections including HIV-1 and its distribution would be easy and economical. Thus the development of potent adjuvant of DNA elicited immune response is of great epidemiological and economical importance.