Role of IRFs in the Innate Response to HIV

描述（由申请方提供）：拟议研究的重点是确定IRF转录因子在对HIV-I感染的先天反应中的作用。在过去的几年里，我们已经确定和表征了三个新的IRF：IRF-3，IRF-5和IRF-7。我们已经证明，这些因子可以作为病毒介导的信号传导的直接转换器，并在感染细胞中诱导I型干扰素（IFN）和几种趋化因子方面发挥关键作用。我们和其他人已经表明，在感染RNA和DNA病毒的细胞中，这些存在于细胞质中的因子被磷酸化并易位到细胞核，在那里它们形成组装在IFNA和IFNB基因启动子上的转录复合物的一部分。还有越来越多的证据表明，不同的病毒靶向细胞IRF-3和IRF-7的激活和功能，以克服先天免疫应答。对HIV-1感染的免疫控制的研究集中在适应性细胞抗病毒反应的作用上，而对先天免疫机制在HIV-1感染控制中的作用知之甚少。为了填补这一空白，提出的研究的目的是分析IRF在HIV介导的先天反应中的作用。该研究有三个目标：目标1。IRF-3、IRF-5和IRF-7在HIV复制中的作用在这里，我们将确定IRFs的表达水平及其组成型活性突变体如何调节HIV-1的复制和感染。目标二。通过HIV-1介导的信号传导的IRF的翻译后活化。在这项研究中，我们将研究HIV-1刺激的信号级联是否诱导IRFs的磷酸化，它们的核转位和转录激活。目标3. Nef在IRF因子表达/激活中的作用。我们将确定Nef是否刺激iRF-3、5或7的表达并诱导它们的磷酸化和核转位，或者它是否阻断这些IRF的功能。这项研究应该提供一些基本的洞察先天反应在控制HIV-1感染的作用。更好地了解最初的抗病毒免疫对于理解HIV-1的发病机制至关重要，并可能有助于开发新的抗病毒疗法。

DESCRIPTION (provided by applicant): The focus of the proposed study is to determine the role of IRF transcription factors in the innate response to HIV-I infection. Over the past few years we have identified and characterized three novel IRFs: IRF-3, IRF-5 and IRF-7. We have shown that these factors serve as direct transducers of virus mediated signaling and play a critical role in the induction of Type I interferons (IFN) and several chemokines in infected cells. We and others have shown that in cells infected both with RNA and DNA viruses these factors that reside in the cytoplasm are phosphorylated and translocated to nucleus where they form part of the transcription complex assembled on the promoters of IFNA and IFNB genes. There is also growing evidence that different viruses target the activation and function of cellular IRF-3 and IRF-7 to overcome the innate immune response. Studies of the immune control of HIV-1 infection has focused on the role of adaptive cellular antiviral response, while much less is known about the role of innate immune mechanisms in the control of HIV-1 infection. To fill this gap, the aim of the proposed study is to analyze the role of lRFs in the HIV mediated innate responses. The study has three aims: Aim1. The role of IRF-3, IRF-5 and IRF-7 in HIV replication. Here we shall determine how the expression levels of IRFs and their constitutively active mutants modulate HIV-1 replication and infection. Aim 2. Postranslational activation of IRF by HlV-1 mediated signaling. In this study we shall examine whether HIV-1 stimulated signaling cascades induce phosphorylation of IRFs, their nuc]ear translocation and transcription activation. Aim 3. The role of Nef in expression/activation of IRF factors. We shall determine whether Nef stimulates expression of iRF-3, 5 or 7 and induces their phosphoryJation and nuclear translocation or whether it blocks the function of these IRFs. This study should provide some basic insight into the role of innate response in control of HIV-1 infection. A better understanding of the initial antiviral immunity is essential for understanding HIV-1 pathogenesis and may be instrumental for developing new antiviral therapies.